bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–03–15
fifty papers selected by
Luca Bolliger, lxBio
  1. ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.
  2. Mesenchymal stem cells and the central nervous system: historical perspectives and future directions.
  3. Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.
  4. TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral Sclerosis.
  5. Lipid Messengers: Mechanisms and Clinical Applications of Exosomal Lipids in Neurodegenerative Diseases.
  6. Brain Folding Trajectories in Amyotrophic Lateral Sclerosis.
  7. The role of MyD88 in the nervous system: Neuronal functions, implications in neurological diseases, and therapeutic potential.
  8. Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis.
  9. PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.
  10. Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review).
  11. "A rough and swirling sea": Voicing Amyotrophic Lateral Sclerosis through discourse analysis.
  12. Quantification of Tongue Motor Dysfunction in Amyotrophic Lateral Sclerosis Using a Smartphone-Based Task and Deep Learning.
  13. [Immune Cells and Proteins Associated with Disease Progression in Amyotrophic Lateral Sclerosis: New Insights from Multiomics Analyses].
  14. Advancement in therapeutic application of quantum dots in amyotrophic lateral sclerosis: current opportunities and challenges.
  15. TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure.
  16. HML-2 env knockdown by AAV9-mediated miRNAs attenuates amyotrophic lateral sclerosis-like manifestations in mice.
  17. Respiratory alterations in patients with amyotrophic lateral sclerosis.
  18. Inflammation-Associated Mechanisms of Blood-Brain Barrier Disruption and Depression Pathogenesis in People with and Without HIV.
  19. Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study.
  20. The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer's and Parkinson's disease: a systematic review and meta-analysis.
  21. Serum Trace Elements and Their Associations with Disease Progression and Survival in Sporadic Amyotrophic Lateral Sclerosis: Insights from a Chinese Cohort.
  22. TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.
  23. Long-wave infrared imaging for respiratory rate measurement in a patient with amyotrophic lateral sclerosis: A case report.
  24. Clinical Validation of Plasma p-217tau in Neurological Diseases.
  25. Exercise pressor reflex in Amyotrophic lateral sclerosis patients.
  26. Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis.
  27. cGAS inhibition delays TDP-43-driven ALS Pathogenesis.
  28. Distinct Prescription Patterns Emerge Years Before ALS Diagnosis: A Nationwide Registry-Based Study.
  29. Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset.
  30. ALS untangled #83: clenbuterol.
  31. Oral Health in Amyotrophic Lateral Sclerosis: Feasibility of Oral Screening and Determinants of Poor Outcomes.
  32. Non-invasive ventilation support during feeding tube placement in amyotrophic lateral sclerosis patients with moderate to severe ventilatory impairment: an update.
  33. Gut-Derived Metabolites and Cognitive Health: Roles of Short-Chain Fatty Acids and Trimethylamine N-oxide.
  34. Neuroprotective Effects of Esketamine in Central Nervous System Disorders: Mechanisms and Cellular Targets.
  35. Landscape of Protein Post-Translational Modifications in Age-Related Neurodegenerative Disorders: Implications in Protein Aggregation, Altered Cellular Processes, and Therapeutics.
  36. Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
  37. Complement dysregulation in multiple sclerosis: emerging mechanisms and translational therapeutic opportunities.
  38. Carbon dots penetrating the blood-brain barrier for central nervous system nanomedicine.
  39. A Nasal Hydrogel Combining Metformin and Curcumin for Potential Nose-to-Brain Therapy in Neurodegenerative Disorders.
  40. Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.
  41. Impact of the Combination of Epigallocatechin Gallate and Ellagic Acid Supplemented with Ketone Bodies on Energetic Restoration of Mitochondrial Dysfunction and Metabolic Inefficiencies in Patients with Multiple Sclerosis: A Review.
  42. Elucidating the molecular targets in Alzheimer's disease: Advances and therapeutic implications.
  43. An electrochemical enzyme-linked immunosorbent assay for interleukin 18 quantification in 3D skin models derived from ALS patients.
  44. Effects of different exercise modalities on four major neurodegenerative diseases and their molecular mechanisms.
  45. From Polyphenols to Prodrugs: Bridging the Blood-Brain Barrier with Nanomedicine and Neurotherapeutics.
  46. Claudins in Retinal Disease: Beyond Barrier Integrity to Signaling and Therapy.
  47. Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.
  48. An Unusual Presentation of Juvenile Amyotrophic Lateral Sclerosis with Superoxide Dismutase 1 Mutation: Subacute Bulbar Palsy With Asymmetric Limb Weakness.
  49. Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical.
  50. Comparison of neonatal systemic and intracerebroventricular AAV9 gene therapy delivery demonstrating improved behavioral and phenotypic outcomes in a mouse model of Niemann-Pick disease, type C1.
  1. J Neurosci. 2026 03 11. pii: e0263252026. [Epub ahead of print]46(10):
    ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.
    Cailyn M Perry, Dale D O Martin.
      Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are lethal neurodegenerative diseases affecting motor function. Though their etiology and pathology are distinct, recent evidence suggests commonalities between TAR DNA-binding protein (TDP-43), which is associated with 97% of ALS cases, and huntingtin (HTT), the causative protein of HD. ALS is a heterogeneous, lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, as well as brainstem and spinal cord degeneration. The causes of ALS are complex, variable, and, in some cases, unknown, but most cases involve mislocalization of the protein TDP-43. In contrast, HD is a monogenic, autosomal dominant, lethal neurodegenerative disease caused by polyglutamine expansion in HTT protein and characterized by the progressive loss of neurons in the brain, particularly in the striatum, which results in motor, cognitive, and behavioral changes. Although HD is not typically associated with motor neuron loss, recent evidence suggests a link between HTT and TDP-43 within the context of both ALS and HD, as well as links to related neurodegenerative diseases, such as frontotemporal dementia (FTD) and spinocerebellar ataxia type 2 (SCA2). Herein, we discuss confirmed cases of concurrent ALS and HD and the overlap of underlying disease mechanisms that potentially contribute to the onset and progression of these two devastating neurodegenerative diseases, with a focus on commonalities between TDP-43 and HTT. We propose that elucidating these commonalities will aid in the identification of broad-spectrum disease risk factors and potential overlapping treatment targets.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0263-25.2026
  2. Front Mol Neurosci. 2026 ;19 1742864
    Mesenchymal stem cells and the central nervous system: historical perspectives and future directions.
    Christopher Y Mazurek, Julia K Kaniuk, Christopher S Ahuja.
      Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.
    Keywords:  MSC secretome; central nervous system; clinical trials; immunomodulation; inflammation; mesenchymal stem cell; neurodegeneration; regenerative medicine
    DOI:  https://doi.org/10.3389/fnmol.2026.1742864
  3. medRxiv. 2026 Mar 06. pii: 2026.03.06.26347446. [Epub ahead of print]
    Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.
    Helena Cortes-Flores, Georgina Torrandell-Haro, Roberta Diaz Brinton.
       Introduction: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.
    Methods: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.
    Results: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < .0001) and was equally effective in both sexes. Risk reduction was observed for each individual disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the largest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (<1 year) to 0.25 (>6 years). Risk reduction was strongest in older participants (75-79 years).
    Discussion: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with substantially reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.
    DOI:  https://doi.org/10.64898/2026.03.06.26347446
  4. Cells. 2026 Feb 27. pii: 420. [Epub ahead of print]15(5):
    TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral Sclerosis.
    Li-Hong Mao, Yu-Ning Song, Jing-Qi Zhang, Yun-Ting Shao, Zhang-Li Wang, Na Yang, Wen-Xuan Zhang, Ying-Rui Zhang, Xiao-Yan Gao, Jia-Yi Li, Lin Yuan.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor neurons. T cell intracellular antigen 1 (TIA1) is a risk gene for ALS pathogenesis. To elucidate TIA1-mediated disease mechanisms, a mouse model recapitulating clinical and pathological features of ALS is needed. TIA1 mutations are rare in human ALS, and mutations are heterozygous, while this study uses a homozygous TIA1 mutant mouse model to amplify pathogenic effects for experimental tractability.
    METHODS: To explore the mechanisms by which mutant TIA1 causes ALS neurodegeneration, we generated a TIA1 mutant mouse by introducing ALS-causing mutations into the endogenous animal via cytosine base editors. Next, behavioral experiments (open-field and rotarod tests) assessed motor function and analyzed pathologies using morphological assessments.
    RESULTS: Our TIA1Δ mouse model phenocopies select pivotal features of ALS, including TAR DNA-binding protein 43 (TDP-43) accumulation, motor neuron loss, neuroinflammation in the lumbar spinal cord, and muscle atrophy. Notably, this homozygous mutation design with reduced TIA1 expression differs from human heterozygous TIA1 mutations.
    CONCLUSIONS: This work provides a foundation for understanding the TIA1-ALS relationship and for developing strategies to treat this intractable neurodegenerative disorder. Caution is warranted extrapolating findings to human ALS pathogenesis due to model design differences.
    Keywords:  TDP-43; TIA1; amyotrophic lateral sclerosis; mouse model; neurodegenerative disease; neuroinflammation
    DOI:  https://doi.org/10.3390/cells15050420
  5. Mol Neurobiol. 2026 Mar 14. pii: 499. [Epub ahead of print]63(1):
    Lipid Messengers: Mechanisms and Clinical Applications of Exosomal Lipids in Neurodegenerative Diseases.
    Yiyin Zhao, Minjie Pan, Songbin He, Xiaojing Zhou.
      Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, represent an escalating global health burden owing to their complex pathophysiology and limited therapeutic options. Exosomes, nanoscale extracellular vesicles (30-150 nm) capable of crossing the blood-brain barrier (BBB), have emerged as critical mediators of intercellular communication in the central nervous system. While research has predominantly focused on exosomal proteins and nucleic acids, the functional significance of exosomal lipids in neurodegeneration is increasingly recognized. This review outlines the biological characteristics of exosome lipids. Then, we focus on three core mechanisms: how lipid imbalance drives neuronal damage (including membrane dysfunction, lipid peroxidation, and mitochondrial energy crisis), how the lipid-mediated inflammatory network regulates microglial activation and BBB integrity, and how the lipid microenvironment affects the folding, aggregation, and cross-cell transmission of pathological proteins. Critically, these mechanisms form a mutually reinforcing vicious cycle, jointly driving the progression of the disease. Based on this framework, we have summarized the specific alterations of exosomal lipids in diseases such as Alzheimer's disease and Parkinson's disease. The clinical potential of exosomal lipids as liquid biopsy biomarkers and drug delivery carriers is discussed, alongside current challenges including technical standardization, heterogeneity analysis, and quantitative accuracy. A comprehensive understanding of exosomal lipid dynamics is essential for developing novel diagnostic and therapeutic strategies for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Exosomal lipids; Lipidomic; Neurodegenerative diseases; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-026-05794-z
  6. Hum Brain Mapp. 2026 Mar;47(4): e70449
    Brain Folding Trajectories in Amyotrophic Lateral Sclerosis.
    Canadian ALS Neuroimaging Consortium (CALSNIC)
      Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease, and neuroimaging markers offer a promising avenue to capture this variability. Cortical folding alterations in ALS remain largely unexplored despite growing interest in neuroimaging markers of the disease. This study is the first whole-brain investigation of sulcal morphometry in ALS. A total of 222 individuals diagnosed with ALS and 194 healthy controls (HC) were recruited through the Canadian ALS Neuroimaging Consortium (CALSNIC) for a longitudinal investigation. Using T1-weighted MRI processed with FreeSurfer and BrainVISA, we extracted cortical thickness and four sulcal features: width, mean depth, surface area, and length, across 123 sulci. We identified widespread alterations in ALS, with 19 sulci showing increased width and length alongside reduced depth and surface area, primarily in frontal and parietal regions surrounding the motor strip. The central sulcus (CS) emerged as the most consistently affected region, displaying bilateral widening and reduced depth, changes that closely tracked motor decline. Longitudinal analyses revealed progressive widening and reduced depth and surface area of the CS. These alterations closely tracked the progression of motor symptoms over the course of the disease and aligned with regional cortical thickness alterations. Our findings demonstrate that brain folding patterns, and in particular CS, are altered in ALS and correlate with clinical progression, resembling the neurodegenerative pattern of the disease. By revealing complementary and sensitive changes, sulcal-based metrics may offer promising neuroimaging biomarkers for early detection, prognosis, and patient stratification in ALS.
    Keywords:  amyotrophic lateral sclerosis; brain folding; sulcal morphometry
    DOI:  https://doi.org/10.1002/hbm.70449
  7. Pharmacol Ther. 2026 Mar 11. pii: S0163-7258(26)00043-4. [Epub ahead of print] 109016
    The role of MyD88 in the nervous system: Neuronal functions, implications in neurological diseases, and therapeutic potential.
    Hai-Li Pan, Jia-Yi Ge, Zi-Ang Zhang, Jia-Huan Xu, Jia-Ni Wu, Yi Ju, Xi-Yu Zhang, Zuo-Jie Jiang, Yong Chen, Yun-Zhao Xu, Xing-Jun Liu.
      Myeloid differentiation primary response 88 (MyD88), a central adaptor protein governing Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling cascades, is increasingly recognized as a pivotal mediator of neuroimmune interactions and neuromodulation. Beyond its canonical immune functions, emerging evidence reveals widespread MyD88 expression throughout the nervous system, where it plays functional roles in both glial populations and neuronal networks. While previous reviews have largely focused on glial mechanisms, recent studies highlight a complex, often overlooked aspect: the dual role of neuronal MyD88 signaling in orchestrating neurodevelopment while paradoxically driving neuroinflammation and synaptic dysregulation. Given the growing interest in innate immunity's involvement in central nervous system (CNS) diseases, a timely synthesis of MyD88 biology-from molecular mechanisms to therapeutic implications-is essential to bridge the fields of immunology and neuroscience. This article provides a comprehensive review of MyD88, synthesizing contemporary insights into its multifaceted regulatory roles in neural homeostasis and pathogenesis. We place particular emphasis on its mechanistic contributions to brain injury, chronic pain, and neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Furthermore, we evaluate innovative therapeutic approaches targeting MyD88-dependent pathways, highlighting recent pharmacotherapeutic advances and their neuroprotective potential. Finally, addressing the limitations of current strategies, we advocate for a new framework focused on developing therapeutics with increased cell selectivity, thereby advancing the precision and translational potential of MyD88-targeted interventions.
    Keywords:  Brain injury; Chronic pain; MyD88; Neurodegenerative disease; Neuroinflammation; TLR/IL-1R signaling
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109016
  8. Brain. 2026 Mar 10. pii: awag096. [Epub ahead of print]
    Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis.
    Cyril Jones Jagaraj, Sayanthooran Saravanabavan, Sonam Parakh, Mrithulabashini Jayakumar, Sara Assar Kashani, Sina Shadfar, Prachi Mehta, Shashi Gautam, Fabiha Farzana, Alexandra K Suchowerska, Kuok Yap, Marta Vidal, Audrey M G Ragagnin, Md Shafi Jamali, Shu Yang, Thomas Fath, David Craik, Julie D Atkin.
      Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neurodegeneration and developing new therapeutic targets in these conditions. Cofilin is a multi-functional protein with a crucial role in regulating the actin cytoskeleton. Actin has important neuronal-specific activities in dendritic spines, axonal growth cones and synapses and it is in constant equilibrium between two forms: monomeric globular actin (G-actin) and polymeric filamentous actin (F-actin). Cofilin controls actin dynamics by depolymerising and severing actin filaments. When cofilin is phosphorylated (at Serine-3) by LIM kinase1 (LIMK1), it becomes inactive, leading to production of more F-actin. Defects in cofilin are well described in other neurodegenerative disorders, unlike in ALS. We examined phosphorylation of cofilin and actin dynamics in post-mortem spinal cord tissue from sporadic ALS (SALS) patients, the TDP-43 rNLS8 transgenic mouse model, and NSC34 motor neuronal cells expressing cytoplasmic TDP-43. F-actin was pharmacologically stabilized to mimic cofilin hyperphosphorylation, and TDP-43 pathology was assessed. Neuronal cells were treated with a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN), and TDP-43 pathology and apoptosis were evaluated. Here, we show that cofilin is hyper-phosphorylated in human ALS and disease models compared to controls. This was detected in spinal motor neurons from sporadic ALS (SALS) patients and a TDP-43 mouse model (rNLS8) displaying key ALS phenotypes, and in motor neuronal NSC34-cells expressing cytoplasmic TDP-43. Supporting this observation, more F-actin relative to G-actin was present in cortical/spinal cord lysates from SALS patients and TDP-43 rNLS8 mice, and NSC34-cells expressing TDP-43. We also show that mimicking cofilin hyperphosphorylation by pharmacological stabilization of F-actin induced TDP-43 pathology: cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, and fragmentation, and promoted its recruitment into stress granules (SGs). Furthermore, we detected increased levels of LIMK1 phosphorylation and tropomyosin isoforms 4.1 and 4.2 in SALS patients. These findings reveal aberrant cofilin hyperphosphorylation disrupts actin dynamics, triggering TDP-43 pathology and SG recruitment in SALS. They imply that preventing cofilin phosphorylation is a novel therapeutic strategy applicable to most ALS cases. Treatment of neuronal cells with the S3A peptide prevented features of TDP-43 pathology and apoptosis compared to control peptides. These findings thus describe a novel pathogenic mechanism producing TDP-43 pathology, applicable to most ALS cases and other neurodegenerative diseases.
    Keywords:  ALS/MND; LIMK1 dysregulation; TDP-43 pathology; actin dysregulation; cofilin hyperphosphorylation and dysregulation
    DOI:  https://doi.org/10.1093/brain/awag096
  9. Brain. 2026 Mar 11. pii: awag092. [Epub ahead of print]
    PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.
    Jaskaran Singh, Léa Lescouzères, Charlotte Zaouter, Mathilde Chaineau, Ghazal Haghi, Thomas M Durcan, Shunmoogum A Patten.
      A hexanucleotide (GGGGCC) repeat expansion in C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protein expression. C9orf72 is highly expressed in the cerebellum and growing evidence implicates C9orf72-associated cerebellar pathology across neurodegenerative disorders including ALS/FTD, yet the pathogenic mechanisms remain unresolved. Here, we demonstrate in vivo C9orf72 loss of function leads to cerebellar atrophy, loss of GABAergic interneurons, and depletion of Purkinje and Granule cells. Additionally, we demonstrate that these cerebellar anomalies precede motor defects. Single-cell transcriptomics of the C9orf72-zebrafish brain revealed the downregulation of a purine biosynthetic gene paics in Purkinje cells. Furthermore, we demonstrate the reduced expression of PAICS in the human post-mortem cerebellar sections and iPSC-derived motor neurons from C9orf72 and sporadic ALS patients. Knockout of paics in zebrafish recapitulates cerebellar neuronal loss, neuromuscular junction disruption, motor impairment and widespread DNA damage and repair (DDR) defects including suppression of key DNA repair pathways. Restoring paics expression in C9orf72 zebrafish resolves DNA damage and preserves Purkinje cells and Granule cells, revealing PAICS as a critical mediator of cerebellar degeneration and a promising therapeutic avenue for C9orf72-associated ALS and FTD.
    Keywords:  C9orf72; DNA damage; DNA repair; PAICS; amyotrophic lateral sclerosis; cerebellum; frontotemporal dementia
    DOI:  https://doi.org/10.1093/brain/awag092
  10. Int J Mol Med. 2026 May;pii: 119. [Epub ahead of print]57(5):
    Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review).
    Wenjing Chen, Heng Tian, Ran Wei, Xiaomei Chen, Yiwen Jia.
      Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive loss of neurons. Although the precise pathogenesis of such diseases is complex and multifactorial, several molecular pathways have been implicated, including the aggregation of misfolded proteins, mitochondrial dysfunction, oxidative stress, neuroinflammation and disrupted iron homeostasis. Emerging evidence has underscored the pivotal role of ferroptosis, an iron‑dependent, non‑apoptotic form of cell death, in neurodegenerative disease progression. Ferritin, characterized by a 24‑subunit hollow sphere structure composed of heavy and light chains, plays a key role in the network regulating cerebral iron homeostasis. In response to cellular iron overload, ferritin expression is upregulated to sequester labile iron and mitigate Fenton reaction‑mediated toxicity, thus exerting a cytoprotective function. Paradoxically, ferritin can be degraded via ferritinophagy, a selective autophagic process that releases toxic ferrous iron and directly triggers ferroptosis. This review systematically reviews the role of ferritin within the iron homeostasis network to elucidate the connection between the dysregulation of iron metabolism and the pathological mechanisms of neurodegenerative diseases. The study focused on the potential role of ferritin as a biomarker for early diagnosis, therapeutic strategies targeting ferritin pathways to restore iron homeostasis and the clinical translational value of magnetic resonance imaging‑based non‑invasive quantification of cerebral iron deposition. It is crucial to elucidate the multidimensional roles of ferritin in neurodegeneration to provide a theoretical foundation for precision diagnostic and therapeutic approaches.
    Keywords:  Alzheimer's disease; Parkinson's disease; ferritin; ferritinophagy; ferroptosis
    DOI:  https://doi.org/10.3892/ijmm.2026.5790
  11. J Health Psychol. 2026 Mar 09. 13591053261424031
    "A rough and swirling sea": Voicing Amyotrophic Lateral Sclerosis through discourse analysis.
    Elisa Zambetti, Andrea Greco, Clara Mucci, Simone Belli.
      Amyotrophic Lateral Sclerosis (ALS) is a rare, incurable neurodegenerative disease that leads to death within 5 years of diagnosis and greatly impacts patients' and caregivers' quality of life (QoL). Typically leading to death within 5 years, ALS underscores the need for emotional and psychological support. This study analyzes 118 testimonies from patients (n = 67), informal caregivers (n = 41), and formal caregivers (n = 10), with a gender-balanced sample (n = 67 women), using discourse analysis. Narratives reveal a complex emotional landscape of suffering and resilience, showing ALS as a disruptive force that prompts reevaluation of roles and life stories. Shared support is crucial within families and social settings. Many testimonies express a desire to raise awareness and fund research. Understanding ALS through these stories offers insights into the psychological, emotional, cultural, and social challenges, essential for developing tailored interventions to support psychological well-being.
    Keywords:  amyotrophic lateral sclerosis; caregivers; discourse analysis; patients; quality of life
    DOI:  https://doi.org/10.1177/13591053261424031
  12. Sensors (Basel). 2026 Feb 27. pii: 1498. [Epub ahead of print]26(5):
    Quantification of Tongue Motor Dysfunction in Amyotrophic Lateral Sclerosis Using a Smartphone-Based Task and Deep Learning.
    Pedro S Rocha, Duarte Folgado, Vasco A Conceição, Miguel Oliveira Santos, Mamede de Carvalho.
       BACKGROUND: Bulbar dysfunction is a major complication of amyotrophic lateral sclerosis (ALS). This study aimed to develop and validate a simple, smartphone-based task for the objective assessment of tongue movements and to examine their association with clinical variables.
    METHODS: 37 ALS patients and 20 age- and sex-matched controls performed a tongue lateralization task, recorded with a smartphone. A deep-learning U-Net++-based model was used for segmentation and feature extraction. The frequency and maximum amplitude of tongue movements were quantified. Clinical measures included the ALS Functional Rating Scale-revised (ALSFRS-r) bulbar sub-scores, tongue fasciculations, jaw jerk, and tongue "spasticity". Between-group differences and associations between tongue metrics and clinical features were assessed.
    RESULTS: The U-Net++-based model achieved robust segmentation performance. Patients showed lower tongue movement frequency than controls (0.14 vs. 0.40, t = -9.58, p < 0.001). Normalized frequency was associated with dysarthria (t = -3.13, p = 0.003) but not dysphagia (t = -1.05, p = 0.30). Normalized frequency (t = 2.77, p = 0.009) and tongue "spasticity" (t = -2.57, p = 0.015) were both associated with speech performance in a multiple-regression model (R = 0.51, adjusted R2 = 0.43).
    CONCLUSIONS: Our method provides an objective, minimally invasive measure of bulbar function in ALS, which correlates with clinical ratings and may detect subtle impairments not captured by standard assessments. This approach offers a promising tool for remote monitoring and may support more effective disease management.
    Keywords:  amyotrophic lateral sclerosis; bulbar dysfunction; deep learning; dysarthria; tongue
    DOI:  https://doi.org/10.3390/s26051498
  13. Brain Nerve. 2026 Mar;78(3): 285-288
    [Immune Cells and Proteins Associated with Disease Progression in Amyotrophic Lateral Sclerosis: New Insights from Multiomics Analyses].
    Koji Fujita, Naoko Matsui, Yuishin Izumi.
      Disease progression in amyotrophic lateral sclerosis shows substantial individual variability, and immune mechanisms have attracted attention as underlying factors. Immune profiles associated with disease progression were identified using cytokine profiling, proteomics, and single-cell analyses. Peripheral blood mononuclear cells, such as Th17 cells and effector CD8+ T cells, along with inflammation-related proteins, including interleukin-17A and CD94, are associated with disease progression. This review summarizes the findings of multi-omics studies.
    DOI:  https://doi.org/10.11477/mf.188160960780030285
  14. Drug Deliv Transl Res. 2026 Mar 12.
    Advancement in therapeutic application of quantum dots in amyotrophic lateral sclerosis: current opportunities and challenges.
    Vivek Bakshi, Binay Pathak, Ankit Majie, Arya Ghosh, Abhinav Gupta, Neha Jain, Manisha Pandey, Anroop B Nair, Shery Jacob, Papiya Mitra Mazumder, Neelima Sharma, Nimmy Kumari, Bapi Gorain.
      Despite advancements in healthcare settings in developed countries, the early detection and higher mortality rate associated with amyotrophic lateral sclerosis (ALS), a fatal motor neuronal disorder, remain challenging. Recently, quantum dots (QDs) have emerged as a promising nanocarrier in the prognosis and treatment of ALS owing to their unique multifunctional properties. QDs, through their photoluminescence properties upon excitation, can facilitate the identification and real-time monitoring of disease biomarkers. They also act as a nanocarrier for the targeted delivery of therapeutics, avoiding accumulation at the non-targeted sites and minimising toxicity. QDs can be fabricated to conjugate with protein biomarkers linked to ALS, such as specific proteins, nucleic acids, or genetic variants, for the diagnosis of the disease. Such fabrication could lead to enhanced identification and diagnostic patterns of ALS, thereby contributing to improved therapeutic intervention strategies. Furthermore, these tiny structures could be applied in combined biosensor formats to identify ALS-associated biomarkers in body fluids, which would be a highly sensitive diagnostic system. Subsequently, comprehensive multiomics techniques have demonstrated improved identification of newer protein targets associated with neurological complications. Overall, QDs can be explored as a potential tool to identify biomarkers relevant to ALS, diagnose the disease at its early stages, and track the effectiveness of the treatment. The integration of QD with omic-based strategies and network analysis can potentially catalyse a breakthrough in the management of ALS. Therefore, this review aims to explore the application of QDs in ALS diagnosis and management, advancements in research, clinical trials, and patents.
    Keywords:  Amyotrophic lateral sclerosis; Bio-imaging; Nanotechnology; Quantum dots; Theranostic application
    DOI:  https://doi.org/10.1007/s13346-026-02082-0
  15. Cells. 2026 Mar 06. pii: 477. [Epub ahead of print]15(5):
    TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure.
    Francesca Manganelli, Camilla Perfetto, Olga Carletta, Valeria Gerbino.
      Mutations in the TANK-binding kinase 1 (TBK1) gene represent a significant genetic link across the Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) spectrum. As a multifunctional serine/threonine kinase, TBK1 serves as a central orchestrator of the autophagy-lysosome pathway, regulating critical stages from initial cargo recognition and autophagosome biogenesis to vesicle maturation and lysosomal fusion. This review examines the mechanisms by which TBK1 coordinates these diverse autophagic functions. We then focus on how ALS/FTD-associated mutations-ranging from truncating variants causing haploinsufficiency to domain-specific missense mutations-disrupt these essential processes.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); TANK-binding kinase 1 (TBK1); autophagy; frontotemporal dementia (FTD)
    DOI:  https://doi.org/10.3390/cells15050477
  16. Brain. 2026 Mar 14. pii: awag102. [Epub ahead of print]
    HML-2 env knockdown by AAV9-mediated miRNAs attenuates amyotrophic lateral sclerosis-like manifestations in mice.
    Myoung-Hwa Lee, Wenxue Li, Kevon Sampson, Stephanie Choi, Melina Jones, Joseph Steiner, Avindra Nath.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is no cure. While the precise etiology of ALS remains elusive, growing evidence suggests a pathogenic role for human endogenous retrovirus-K (HERV-K) in ALS. Expression of HERV-K subtype HML-2 envelope protein in neurons causes neurotoxicity in vitro and induces ALS-like symptoms in mice. We investigated the use of the Adeno-Associated Virus-9 (AAV9)-mediated artificial microRNA (amiRNA) targeting the HML-2 env gene in an ALS mouse model. From an in vitro screen of amiRNAs targeting the HML-2 env gene three were chosen and inserted in tandem into an AAV9 vector and validated in vitro. This approach provided robust silencing of the transgene, with tandem amiRNA achieving robust reduction in gene and protein expression levels. Its therapeutic effectiveness was tested in an HML-2 Env transgenic mouse model in which the env gene is expressed under the neuron-specific thy1 promoter and develops an ALS-like phenotype. A single intracerebroventricular injection of AAV9 vector encoding the amiRNAs into the mice at postnatal day 1 effectively reduced HML-2 Env expression in the brain and spinal cord at 84 days post-injection which was the longest time point studied. Knockdown of HML-2 env decreased the loss of cortical and spinal motor neurons and alleviated muscle fiber degeneration and fiber type grouping. This led to improved motor function. Our results provide compelling evidence supporting the use of multiple amiRNAs delivered in an AAV9 vector for treating forms of ALS linked to HML-2.
    Keywords:  RNAi; adenovirus; endogenous retroviral elements; gene therapy; motor neuron disease; transposable elements
    DOI:  https://doi.org/10.1093/brain/awag102
  17. Med Clin (Barc). 2026 Mar 11. pii: S0025-7753(26)00015-1. [Epub ahead of print]166(5): 107365
    Respiratory alterations in patients with amyotrophic lateral sclerosis.
    Vanessa Riveiro, Lucía Ferreiro, Romina Abelleira, Nuria Rodríguez-Núñez, María E Toubes, Jorge Ricoy, Tania García-Sobrino, Luis Valdés, Carlos Zamarrón.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and heterogeneous neurodegenerative disease that manifests itself in different phenotypes depending on the anatomical region affected.
    PATIENTS AND METHODS: Retrospective observational study of patients diagnosed with ALS in our healthcare area, classified by phenotypes to assess their relationship with functional respiratory variables, gas exchange, and sleep-related breathing disorders. The search period was from 2014 to 2024.
    RESULTS: Data from 201 patients were analyzed. The overall mean incidence of ALS was 3.8 cases (95%CI: 3.3-4.3)/100,000 inhabitants/year, while the prevalence was 9.4 cases (95%CI: 7.8-11.1)/100,000 inhabitants. The results indicated that the spinal phenotype is the most common (49.3%), while the bulbar phenotype presented greater respiratory involvement, with a lower forced vital capacity (FVC) (86% [IQR: 66.5-98]) and greater nocturnal desaturation CT90 8% (IQR: 2.3-32.5%). Likewise, a prevalence of respiratory disorders during sleep was observed, with approximately 50% mild obstructive sleep apnea (OSA), 30% moderate, and 15% severe. Severe OSA was recorded in 8% of patients with spinal ALS, 14% of patients with bulbar ALS, and 17% with other forms of ALS.
    CONCLUSIONS: The disease significantly affects respiratory function, especially in the bulbar phenotype, and respiratory disturbances during sleep are common. The heterogeneity of ALS highlights the importance of a personalized approach to patient management.
    Keywords:  Alteraciones respiratorias; Amyotrophic lateral sclerosis; Apnea obstructiva del sueño; Clinical forms; Esclerosis lateral amiotrófica; Formas clínica; Hipoventilación nocturna; Nocturnal hypoventilation; Obstructive sleep apnea; Respiratory disturbances
    DOI:  https://doi.org/10.1016/j.medcli.2026.107365
  18. Cells. 2026 Feb 25. pii: 399. [Epub ahead of print]15(5):
    Inflammation-Associated Mechanisms of Blood-Brain Barrier Disruption and Depression Pathogenesis in People with and Without HIV.
    Caitlin Hills, Cristian A Hernandez, Vilma Gabbay, Joan W Berman.
      Depression is the most common neuropsychiatric comorbidity in people with HIV (PWH), with a prevalence of 30-50%, nearly twice that of the general population. Depression is a major cause of disease burden worldwide associated with increased morbidity and mortality in both people with and without HIV. Converging lines of evidence indicate that chronic peripheral inflammation and neuroinflammation, blood-brain barrier (BBB) disruption, and neurocircuit-level changes interact to mediate depression pathogenesis, and that these processes may be especially relevant in PWH. HIV-associated chronic inflammation, which persists despite viral suppression with antiretroviral therapy, may contribute to depression pathogenesis in this population. BBB permeability has been hypothesized to serve as a key mediator for the interaction of peripheral inflammation with the central nervous system in depression pathogenesis. In this review, we will describe the structure and function of the BBB and how peripheral inflammation interacts with cells of the BBB and the mechanisms that lead to increased BBB permeability. We will discuss current research addressing how peripheral inflammation and BBB disruption contribute to depression pathogenesis in people with and without HIV. We will review current techniques for studying BBB permeability in in vitro, animal, and clinical models and outline future directions for ongoing research.
    Keywords:  HIV; blood–brain barrier; cellular mechanisms; depression; neuroimaging; neuroinflammation; neuropsychiatric disorders; peripheral mediators
    DOI:  https://doi.org/10.3390/cells15050399
  19. Lancet Digit Health. 2026 Mar 10. pii: S2589-7500(25)00145-1. [Epub ahead of print] 100963
    Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study.
    Richard J Reimer, Braden Soper, Jennifer L Wilson, Andre R Goncalves, Jose Cadena, Paola Suarez, Amy L Gryshuk, Thomas F Osborne, Kevin V Grimes, Priyadip Ray.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3-5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS.
    METHODS: We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein-protein interaction networks-based algorithm PathFX.
    FINDINGS: The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs.
    INTERPRETATION: To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.
    FUNDING: Congressionally Directed Medical Research Programs, US Department of Defense.
    DOI:  https://doi.org/10.1016/j.landig.2025.100963
  20. Front Aging Neurosci. 2026 ;18 1733682
    The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer's and Parkinson's disease: a systematic review and meta-analysis.
    Ana Flavia F Ferreira, Ana Caroline Santos-Silva, Beatriz Gangale Muratori, Luiz Roberto Britto.
      Microglia are central nervous system immune cells that support brain homeostasis but can adopt harmful roles in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), depending on the disease stage and progression. Thus, targeting microglia through depletion has emerged as a potential therapeutic approach. This systematic review and meta-analysis aim to evaluate the effects of microglial depletion using colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX3397 and PLX5622, in preclinical models of AD and PD. Twenty-six AD and seventeen PD preclinical studies were selected. In PD models, most studies reported neuroprotective effects after microglial depletion, though a few showed detrimental outcomes, particularly with shorter depletion protocols. Notably, almost all studies induced microglial depletion prior to or during disease onset, underscoring a major research gap. Behavioral results were contradictory, as some reported beneficial effects while others showed no effect or worsened behavior. In AD models, results were more variable, but many studies observed reduced neuroinflammation, improved cognition, and decreased amyloid-beta and tau pathology. Meta-analyses showed no overall reduction in dopaminergic neuron loss in PD or amyloid-beta levels in AD, though longer depletion protocols showed more favorable trends in both diseases. Despite the few reports, repopulation following microglial depletion may constitute a promising approach. Microglial depletion, via PLX3397 and PLX5622, may offer therapeutic potential for both AD and PD, although high heterogeneity and variability among studies are a clear limitation. Further studies are needed, particularly those assessing post-onset intervention, sex-specific effects, and broader behavioral and pathological endpoints to better understand the therapeutic potential of microglial modulation.
    Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251075163.
    Keywords:  CSF1-R inhibition; microglial depletion; microglial repopulation; neurodegeneration; neuroprotection
    DOI:  https://doi.org/10.3389/fnagi.2026.1733682
  21. Biomed Environ Sci. 2026 Feb 20. 39(2): 183-191
    Serum Trace Elements and Their Associations with Disease Progression and Survival in Sporadic Amyotrophic Lateral Sclerosis: Insights from a Chinese Cohort.
    Hong Fen Wang, Qiong Hua Sun, Rong Rong Du, Shi Ya Wang, Yan Wang, Jiong Ming Bai, Mao Li, Xu Sheng Huang.
       Objective: The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis (sALS) in China.
    Methods: Clinical data, including diagnostic indicators, clinical characteristics, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores, and serum concentrations of calcium (Ca), magnesium (Mg), iron (Fe), copper (Cu), and zinc (Zn), were collected for hospitalized patients with sALS between 2018 and 2021. Correlation analysis, random forest analysis, and the Gehan-Breslow-Wilcoxon test were used to evaluate the relations between serum trace element levels, disease progression, and survival duration.
    Results: Lower serum Ca levels and higher Mg levels were observed in patients with ALSFRS-R scores < 39. Serum Mg was significantly negatively correlated with ALSFRS-R, trunk, and respiratory scores. Serum Cu and Zn also showed significant negative correlations with the respiratory score, whereas Ca and Fe were not significantly correlated with the ALSFRS-R score. The serum levels of Ca, Mg, Cu, Zn, and Fe remained consistent regardless of the site of disease onset. ALSFRS-R analysis revealed that serum Ca and Mg had a substantial effect on the total ALSFRS-R score, with serum Mg significantly influencing the course of the disease. Notably, low serum Mg levels were associated with extended survival times in patients with sALS.
    Conclusion: Serum levels of Ca and Mg play critical roles in the progression of sALS, and a reduced serum Mg level is related to an extended survival time.
    Keywords:  Amyotrophic lateral sclerosis; Metal/metalloid; Microelement; Risk factor
    DOI:  https://doi.org/10.3967/bes2025.094
  22. EMBO Mol Med. 2026 Mar 10.
    TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.
    Shenrui Guo, Hongfu Jin, Hui Sun, Shuo Huang, Yuanyuan Chen, Yuge Chang, Yu Zhang, Lin Ding, Suyun Chen, Chenglai Fu, Yafu Yin, Weiwei Cheng.
      Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.
    Keywords:  Microglia; Necroptosis; Neuroinflammation; RIPK3; TDP-43
    DOI:  https://doi.org/10.1038/s44321-026-00394-9
  23. J Int Med Res. 2026 Mar;54(3): 3000605261429206
    Long-wave infrared imaging for respiratory rate measurement in a patient with amyotrophic lateral sclerosis: A case report.
    Jaeho Kim, Sungho Kim, Sreya Deb Sreshta, Uday Debnath, Yoo Jin Choo, Min Cheol Chang.
      Respiratory monitoring is important in amyotrophic lateral sclerosis patients as progressive respiratory muscle weakness often leads to respiratory failure. We performed single-case feasibility evaluation of long-wave infrared imaging for noncontact respiratory rate estimation in a hospitalized amyotrophic lateral sclerosis patient and compared it with red-green-blue camera-based optical flow analysis and electrocardiogram-derived respiration. Respiratory rate was assessed using four methods: (a) manual counting as the ground truth; (b) long-wave infrared; (c) red-green-blue; and (d) single-lead electrocardiogram under three lighting conditions (regular, dim, and dark) with three 1-min trials per condition. Estimation accuracy was evaluated using mean absolute error relative to manual counting. Long-wave infrared imaging demonstrated the highest accuracy across all lighting conditions, with mean absolute errors of 1.67, 0.33, and 2.33 breaths per min, respectively. Red-green-blue-based estimation performed moderately well under regular and dim lighting but showed reduced accuracy in darkness, including one failed trial. Electrocardiogram-derived respiration showed the lowest accuracy and greatest variability across conditions. The limitations of the present study include its single-case design and absence of objective flow-based respiratory reference signals. However, this study demonstrates the feasibility and illumination robustness of long-wave infrared-based noncontact respiratory rate estimation in a hospital environment and supports further investigation of this approach for respiratory monitoring in amyotrophic lateral sclerosis patients.
    Keywords:  Respiratory rate; amyotrophic lateral sclerosis; feasibility; long-wave infrared; sensor
    DOI:  https://doi.org/10.1177/03000605261429206
  24. Ann Clin Transl Neurol. 2026 Mar 09.
    Clinical Validation of Plasma p-217tau in Neurological Diseases.
    Takeshi Kawarabayashi, Takumi Nakamura, Ryoma Takahashi, Tetsuya Ueda, Seiji Kinoshita, Chikage Uchida, Takashi Sugawara, Kentaro Hashimoto, Kunihiko Ishizawa, Masakuni Amari, Hiroo Kasahara, Yoshio Ikeda, Masamitsu Takatama, Mikio Shoji.
       OBJECTIVE: Plasma p-217tau is a minimally invasive but specific biomarker for diagnosing Alzheimer's disease (AD). However, its disease specificity remains to be clinically evaluated. We validated the reliability of the p-217tau biomarker in 12 other neurological diseases.
    METHODS: Plasma p-217tau levels were measured in 298 participants, consisting of 81 AD patients, 204 patients with 12 other neurological diseases, and 13 healthy and cognitively unimpaired controls (HCU), using an assay system from Meso Scale Diagnostics. Cerebrospinal fluid (CSF) tau and Aß levels were simultaneously evaluated in AD, amyotrophic lateral sclerosis (ALS), and idiopathic normal pressure hydrocephalus (iNPH).
    RESULTS: Plasma p-217tau levels increased in AD with the clinical stage, but also in ALS and iNPH, leading to them having decreased sensitivity and specificity for diagnosing AD. No increases in plasma p-217tau levels were seen in possible tauopathies or synucleinopathies. CSF and plasma p-217tau levels were strongly correlated in AD, but not in ALS. The plasma p-217tau/CSF p-217tau ratio was inversely higher in ALS than in AD. Active and chronic denervation potentials were associated with plasma p-217tau levels. In iNPH, plasma p-217tau was associated with cognitive dysfunction, but not with gait disturbance or urinary incontinence. CSF p-181tau, total tau, and Aß1-40 levels and the Aß1-40/1-42 ratio were reduced in iNPH.
    INTERPRETATION: ALS and iNPH are two major pitfalls for the clinical application of plasma p-217tau as a biomarker of AD. Lower motor neuron injury in ALS and cognitive dysfunction in iNPH were both found to be associated with elevated plasma p-217tau levels.
    Keywords:  Alzheimer's disease; amyotrophic lateral sclerosis; idiopathic normal pressure hydrocephalus; plasma p‐tau; p‐tau217
    DOI:  https://doi.org/10.1002/acn3.70359
  25. Sci Rep. 2026 Mar 09.
    Exercise pressor reflex in Amyotrophic lateral sclerosis patients.
    Yuko Saeki, Nobuhiro Nakamura, Naoyuki Hayashi.
      
    Keywords:  Exercise pressor reflex; Functional changes; Late-stage ALS patients; Passive exercises; Sensory and autonomic nervous systems
    DOI:  https://doi.org/10.1038/s41598-026-43367-1
  26. Neurol Genet. 2026 Apr;12(2): e200366
    Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis.
    Rogan G Magee, Vivianna M Van Deerlin, Corey T McMillan, Edward B Lee, Lauren B Elman, David John Irwin, Zissimos Mourelatos.
       Background and Objectives: There are no FDA-approved diagnostic biomarkers for amyotrophic lateral sclerosis (ALS). TDP-43 is a known cofactor in the cleavage of long premature microRNAs (miRNAs) into their short, mature products. isomiRs are miRNA variants that differ in their 5' and 3' end points and regulate distinct mRNA targets. In this study, we tested the hypotheses that circulating isomiR profiles differ in the context of TAR DNA-binding Protein pathology and that isomiRs are superior to miRNAs for classification of ALS.
    Methods: We obtained RNA from plasma samples of 14 patients with ALS and 14 age-matched and sex-matched controls for sequencing on a NextSeq 2000. Data were processed using Unique Molecular Identifier tools and a custom pipeline designed to match miRNA variant sequences without mismatches. Differential expression (DE) was identified using DEseq2 at FDR ≤ 0.1. XGBoost classifiers were built using a subset of (Model 1) isomiRs or (Model 2) miRNAs that were present above a median threshold in all sequencing batches. Parameters were tuned using grid search and 10-fold cross-validation while training to distinguish ALS samples from controls among a single large public data set. Models were then validated on in-house samples and 1 publicly available holdout data set.
    Results: Fourteen (0.2%), 355 (2.7%), and 14 (0.7%) isomiRs were differentially expressed in in-house plasma, public ALS plasma, and public ALS serum, respectively. One (0.1%), 94 (5.5%), and 13 (2.4%) miRNAs were differentially expressed, respectively. Model 1 accurately classified in-house ALS plasma and public ALS serum (area under the curve [AUC] = 0.87) and did not distinguish 40 of 41 Alzheimer disease samples from control plasma (GSE215789; AUC = 0.47) or 60 of 77 Parkinson disease samples from control whole blood (GSE180193; AUC = 0.55). In comparison, Model 2 using miRNAs performed worse on in-house plasma (AUC = 0.49).
    Discussion: Analyzing individual isomiRs may improve the performance of circulating noncoding RNAs as diagnostic biomarkers of ALS.
    DOI:  https://doi.org/10.1212/NXG.0000000000200366
  27. bioRxiv. 2026 Feb 26. pii: 2026.02.24.707791. [Epub ahead of print]
    cGAS inhibition delays TDP-43-driven ALS Pathogenesis.
    Yajing Liu, Weixi Feng, Abulimiti Aikedan, Se-In Lee, Maitreyee Bhagwat, Ravi Kumar Nagiri, Man Ying Wong, Sadaf Amin, Wenhui Qu, Jingjie Zhu, Si-Yu Wang, Pearly Ye, Kendra Norman, Guillermo Coronas-Samano, Marta Olah, Hagen U Tilgner, Li Fan, Subhash C Sinha, Li Gan.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by motor neuron loss and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA splicing. However, the upstream modulators of this process remain poorly defined. Here we identify cyclic GMP-AMP synthase (cGAS) as a central mediator of TDP-43 pathology and associated mis-splicing. cGAS expression was elevated in ALS patient brains and enriched across activated microglia. In human iPSC-derived microglia-motor neuron co-cultures, neuronal TDP-43 pathology triggered microglial cGAS activation, whereas pharmacological inhibition with a potent human cGAS inhibitor reduced phosphorylated TDP-43, restored lysosomal and phagocytic programs, normalized microglial reactivity, and reversed TDP-43-associated RNA splicing defects. In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.
    DOI:  https://doi.org/10.64898/2026.02.24.707791
  28. Ann Neurol. 2026 Mar 10.
    Distinct Prescription Patterns Emerge Years Before ALS Diagnosis: A Nationwide Registry-Based Study.
    Magne Haugland Solheim, Trond Riise, Marianna Cortese, Ola Nakken, Ole-Bjørn Tysnes, Jannicke Igland, Kjetil Bjornevik.
       OBJECTIVE: The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre-diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.
    METHODS: We conducted a nested case-control study using nationwide Norwegian registries (2005-2019). ALS cases were individually matched to 100 controls by sex, age, and education level using incidence density sampling. Drug prescription data were gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates up to 10 years before diagnosis, performed lag-time analyses, and used machine learning to predict ALS based on drug prescription patterns.
    RESULTS: We identified 2,084 incident patients with ALS and 208,400 matched healthy controls. Overall, changes in prescription patterns occurred 2 to 3 years before ALS diagnosis. Among specific drug groups, 25 of 42 therapeutic drug classes were prescribed more frequently to patients with ALS than matched controls. Muscle relaxants and bone disease treatments were prescribed significantly more frequently 6 and 5 years before diagnosis, respectively.
    INTERPRETATION: Prescription pattern changes occurred as early as 6 years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78191
  29. FEBS J. 2026 Mar 10.
    Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset.
    Panagiota Georgiadou, Bahriye Erkaya, Michiko Niwa-Kawakita, Merve Oltan, Yigit Kemal Keskin, Egemen Sahin, Harun Öztürk, Fatmanur Tiryaki, Kutay Yildiz, Idil Özgenç, Ezgi Odabasi, Emre Pekbilir, Sukru Anil Dogan, Valérie Lallemand-Breitenbach, Stephanie Vargas, Alain Prochiantz, Elif Nur Firat-Karalar, Hugues de Thé, Umut Sahin.
      Germinal mono-allelic loss-of-function mutations of NEK1 drive amyotrophic lateral sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1t) is aggregation-prone, particularly in alpha-motoneurons (αMNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1t/t). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1wt/t animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1t proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1t puncta in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, yielding dramatic clinical improvement. These observations provide strong proof-of-concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.
    Keywords:  ALS; NEK1; PML; SUMO; ubiquitin
    DOI:  https://doi.org/10.1111/febs.70487
  30. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Mar 08. 1-8
    ALS untangled #83: clenbuterol.
    Adam Burgess, Olivia Allen, Paul Barkhaus, Benjamin Barnes, Michael Benatar, Tulio Bertorini, Robert Bowser, Javier Mascias Cadavid, Gregory T Carter, Merit Cudkowicz, Keelie Denson, Kara Dyckman, Basil Elsharif, Eva Feldman, Juliette Foucher, Timothy Fullum, Jonathan Glass, Benjamin Helmold, Carlayne Jackson, Sartaj Jhooty, Ariah Leday, Elise Mallon, Christopher Mcdermott, Natasha Olby, Lyle Ostrow, Gary Pattee, Erik Pioro, Dylan Ratner, Hemangi Sang, Elia Tito, Fernando Vieira, Paul Wicks, Richard Bedlack, Dario Gelevski.
      ALS Untangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review clenbuterol, a β-2 adrenergic agonist, as a potential treatment for amyotrophic lateral sclerosis (ALS). Clenbuterol has biological effects that could be relevant to the pathophysiology of ALS such as inducing muscle hypertrophy, improving mitochondrial function, and reducing neuroinflammation. Two studies in mouse models of motor neuron disease and two open label trials suggest possible benefits. However these have methodological flaws which limit interpretation. Clenbuterol can have an array of side effects, some severe. Drop-outs due to side effects were very common in one of the ALS trials and in a separate expanded access program. Based on this information, we cannot currently endorse clenbuterol as an ALS treatment, but we do hope to see further studies of it, or another long acting β-2 adrenergic agonist in people with ALS.
    Keywords:  ALS; clenbuterol; muscle atrophy; neurodegeneration; β-2 adrenergic agonist
    DOI:  https://doi.org/10.1080/21678421.2026.2638588
  31. Muscle Nerve. 2026 Mar 11.
    Oral Health in Amyotrophic Lateral Sclerosis: Feasibility of Oral Screening and Determinants of Poor Outcomes.
    Lauren Tabor Gray, Raquel Garcia, Cassandra Gubala, Eden Pressley, Radleigh Santos, Eduardo R Locatelli, Michelle Madera.
       INTRODUCTION: Oral hygiene represents a modifiable risk factor for systemic health and pulmonary complications yet is not routinely addressed in ALS care. This study aimed to examine the relationships between oral health, disease severity and determinants of health in people living with amyotrophic lateral sclerosis (pALS), and to identify key predictors of oral hygiene outcomes.
    METHODS: Individuals with ALS completed an oral hygiene and bulbar screening during their multidisciplinary appointment. Disease demographics, determinants of health, oral health outcomes and bulbar disease outcomes were collected. Descriptives and one sample t-tests were performed to compare oral hygiene outcomes with healthy reference values. Multiple regression analyses were conducted to assess the relationship between disease demographics and oral health.
    RESULTS: Sixty-two pALS aged 64.0 (+/- 10.8), 40% female, 31% Hispanic/Latino and 37% bulbar onset disease were enrolled. Compared to healthy reference values, plaque index (M = 1.45, SD = 0.52, p < 0.0001), gingival index (M = 1.25, SD = 0.46, p < 0.0001) and bleeding on probing (M = 35.26%, SD = 26.1, p < 0.0001) were elevated in pALS. Lack of dental insurance was a significant predictor of bleeding on probing (BOP) (p = 0.001), plaque (p = 0.006) and gingival scores (p = 0.001). ALSFRS-R (p < 0.03) was also predictive of greater plaque, and care partner status (p < 0.04), and age (p < 0.02) were predictors BOP. Ethnicity and dysphagia severity were not significant predictors.
    DISCUSSION: Oral health screenings conducted during routine multidisciplinary visits identified periodontal disease in pALS, representing a feasible and immediately actionable pathway to improve oral care outcomes in pALS.
    Keywords:  amyotrophic lateral sclerosis; bulbar; dental; motor neuron disease; oral health
    DOI:  https://doi.org/10.1002/mus.70213
  32. Panminerva Med. 2026 Mar;68(1): 10-18
    Non-invasive ventilation support during feeding tube placement in amyotrophic lateral sclerosis patients with moderate to severe ventilatory impairment: an update.
    Paolo Banfi, Marian Dimabuyu-Francisco, Antonello Nicolini, Elena Compalati, Agata Lax, Eleonora Volpato, Giancarlo Garuti, Gloria Leonardi, John R Bach, Paolo Solidoro.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, leading to muscle weakness and respiratory issues. Enteral nutrition is used in ALS patients when they experience severe weight loss, dysphagia, dehydration, or a risk of aspiration pneumonia. Noninvasive ventilation (NIV) is essential for managing respiratory failure in ALS patients, especially during feeding tube placement procedures. This narrative review compares percutaneous endoscopic gastrostomy (PEG), percutaneous radiologic gastrostomy (PRG), and radiologically inserted G-tube (RIG) in ALS patients receiving NIV. Studies were found through electronic database searches of Medline and Embase from 2000 to June 2025, including the Cochrane Central Register of Controlled Trials (CENTRAL), EBSCO Online Research Database, and Scopus. The main outcome was the occurrence of adverse events during and within thirty days after gastrostomy tube placement in NIV. Eleven studies involving NIV during PEG/RIG procedures were included. NIV during PEG, RIG, or PRG placement seems to be safe for ALS patients, with few adverse events reported, though future studies with higher methodological quality are needed. Additionally, the review highlights the benefits of better nutritional support, improved quality of life, interdisciplinary teamwork, increased survival rates, and personalized care.
    DOI:  https://doi.org/10.23736/S0031-0808.26.05313-9
  33. Cureus. 2026 Feb;18(2): e103206
    Gut-Derived Metabolites and Cognitive Health: Roles of Short-Chain Fatty Acids and Trimethylamine N-oxide.
    Dharmendra Kumar Gupta, Rakesh Kumar.
      The gut microbiota has emerged as an important regulator of host physiology, extending well beyond digestion and metabolism. Increasing attention has focused on the gut-brain axis, a bidirectional communication network linking the gastrointestinal tract and the central nervous system. Among the many microbial metabolites implicated in gut-brain signalling, short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO) have attracted particular interest because of their potential roles in neuroinflammation, vascular dysfunction, and cognitive decline. This narrative review synthesizes current evidence linking SCFAs and TMAO to cognitive health, drawing on human observational studies, experimental animal models, and mechanistic and secondary syntheses. Human data remain limited and largely observational. Altered gut microbiota composition and reduced SCFA levels have been reported in Parkinson's disease and have been associated with disease severity and neurological phenotypes. In parallel, TMAO has been detected in human cerebrospinal fluid and shown to interact with the blood-cerebrospinal fluid barrier, establishing biological plausibility for central nervous system exposure. Observational studies further link circulating TMAO levels with Alzheimer's disease biomarkers, mild cognitive impairment, and dementia-related neuroimaging features. Experimental evidence provides more direct support. TMAO supplementation promotes brain aging, cognitive impairment, and neuropathological changes in mouse and rat models. In contrast, SCFAs, particularly butyrate, exert neuroprotective effects in models of Alzheimer's disease, Parkinson's disease, and systemic inflammation, with improvements in memory and reductions in pathological markers. Mechanistic studies suggest that SCFAs may modulate immune responses, preserve blood-brain barrier integrity, and regulate microglial activity, whereas TMAO has been linked to endothelial dysfunction, oxidative stress, and neurovascular impairment. Taken together, available evidence supports biologically plausible but still preliminary roles for gut-derived metabolites in cognitive health. SCFAs appear broadly neuroprotective, while TMAO shows adverse associations, particularly in preclinical models. Human causality remains unproven, and clinical translation is premature. Well-designed longitudinal and interventional studies are required before these metabolites can be considered reliable biomarkers or therapeutic targets.
    Keywords:  alzheimer's disease; blood-brain barrier; cognitive decline; gut microbiota; gut-brain axis; mild cognitive impairment; neurodegeneration; neuroinflammation; short-chain fatty acids; trimethylamine n-oxide
    DOI:  https://doi.org/10.7759/cureus.103206
  34. Basic Clin Pharmacol Toxicol. 2026 Apr;138(4): e70221
    Neuroprotective Effects of Esketamine in Central Nervous System Disorders: Mechanisms and Cellular Targets.
    Chendi Zhao, Yan Wang, Jinglang Wu, Hong Cheng.
      Esketamine (ESK), the dextrorotatory enantiomer of ketamine, is an antagonist of the N-methyl-D-aspartic acid (NMDA) receptor. ESK is considered an effective anesthetic because of its ability to mitigate postoperative pain and opioid use. Recently, it has attracted significant research attention for its fast-acting antidepressant effects. Given the advantages of ESK in both perioperative and postoperative contexts, foundational research into this molecule is progressively moving forward. Accumulating evidence suggests that ESK possesses anti-inflammatory, antiapoptotic and antioxidant characteristics in various diseases. This review summarizes the neuroprotective effects of ESK in central nervous system (CNS) disorders. ESK-mediated cellular processes, including neuronal apoptosis, microglial polarization and astrocytic functions, are also summarized. In addition, the underlying molecular mechanisms of ESK are discussed, with a focus on inflammatory pathways and signalling cascades in neurological disorders.
    Keywords:  central nervous system; esketamine; inflammation; neuroprotection; signalling pathway
    DOI:  https://doi.org/10.1111/bcpt.70221
  35. ACS Omega. 2026 Mar 03. 11(8): 12865-12885
    Landscape of Protein Post-Translational Modifications in Age-Related Neurodegenerative Disorders: Implications in Protein Aggregation, Altered Cellular Processes, and Therapeutics.
    Akash Kumar Singh, Tapas K Kundu.
      Accumulation of aggregated or nonfunctional proteins during the aging process is a common hallmark of degenerating neurons in various neurodegenerative disorders. Post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and ubiquitination, etc. in combination with the protein quality control machinery such as autophagy and proteasome systems are essential for the degradation of these toxic aggregates, to maintain normal protein turnover and function of neurons. Abnormal protein quality control machinery primarily mediated by altered post-translational modifications of various proteins are linked to neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and many others. Accumulating evidence from the past two decades shows that targeting these PTMs with various small molecule activators or inhibitors restores synaptic and cognitive processes associated with these neurodegenerative diseases. Here, in this review, we highlight how these PTMs affect the accumulation and aggregation of nonfunctional proteins in various neurodegenerative diseases. Also, we highlight the current advances in exploring small molecule modulators of modifying enzymes as therapeutic options for these diseases.
    DOI:  https://doi.org/10.1021/acsomega.5c00905
  36. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2514355123
    Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
    Yan Yan, Xinming Wang, Hanna Jeon, Teresa R Kee, Khoi D Tran, Hyunkyoung Lee, Xingyu Zhao, Tian Liu, Simon S Wing, Jung-A A Woo, David E Kang.
      Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, & CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of usp19 mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.
    Keywords:  ALS; ER stress; FTD; TDP-43; USP19
    DOI:  https://doi.org/10.1073/pnas.2514355123
  37. Trends Pharmacol Sci. 2026 Mar 11. pii: S0165-6147(26)00039-8. [Epub ahead of print]
    Complement dysregulation in multiple sclerosis: emerging mechanisms and translational therapeutic opportunities.
    Nemat Khan, Zikra M Zakriya, Pamela McCombe, Trent M Woodruff.
      The complement system is a conserved network of plasma and membrane-associated proteins that supports immune defense and tissue homeostasis. In multiple sclerosis (MS), persistent complement activation contributes to neuroinflammation, demyelination, and axonal injury. However, the translation of complement-targeted therapies for MS treatment has been limited, largely due to uncertainty surrounding the complex and context-dependent roles of complement pathways within the central nervous system. This review integrates the latest preclinical and clinical insights to delineate pathogenic and reparative complement pathways and to support the stratification of MS phenotypes using complement biomarkers and signatures. We further review approved and emerging complement inhibitors with neurological relevance, focusing on their translational implications for MS. Together, this integrated framework may guide the rational design of future complement-targeted MS trials.
    Keywords:  complement system; multiple sclerosis; neuroinflammation; therapeutic targets; translational pharmacology
    DOI:  https://doi.org/10.1016/j.tips.2026.02.006
  38. Theranostics. 2026 ;16(9): 5016-5043
    Carbon dots penetrating the blood-brain barrier for central nervous system nanomedicine.
    Wubshet Mekonnen Girma, Girum Getachew Demissie, Shewaye Lakew Mekuria, Shamsa Kizhepat, T M Subrahmanya, Akash S Rasal, Binyam Abdu Berhe, Gangaraju Gedda, Yoo-Jin Park, Jia-Yaw Chang, Myung-Geol Pang.
      Central nervous system (CNS) diseases are challenging to treat because of the blood-brain barrier (BBB), formed by tight junctions that limit the transcellular transport of therapeutic drugs. Carbon dots (CDs) have emerged as versatile nanotheranostic platforms for the targeting, diagnosis, and treatment of CNS diseases owing to their ultrasmall size, intrinsic photoluminescence, tunable surface chemistry, and biocompatibility. Surface modifications of CDs with targeting ligands, polymer coatings, biomimetic membranes, and exosome-like molecules enable BBB penetration and selective brain accumulation. CDs also support multimodal imaging techniques, such as fluorescence, magnetic resonance, and photoacoustic imaging, for early disease detection and real-time therapeutic monitoring. In addition, their ability to deliver drugs, genes, and therapeutic agents, combined with their antioxidant, anti-inflammatory, photothermal, photodynamic, and sonodynamic properties, highlights their potential for the integrated diagnosis and treatment of CNS diseases. This review systematically summarizes the background of CDs, the design of BBB-penetrating CDs, and their applications in tumor diagnosis, treatment, and imaging-guided cooperative therapies for CNS diseases. Finally, current obstacles and future perspectives are discussed. This review provides a valuable reference for the rational design of BBB-penetrating CDs for the precise treatment of neurological disorders and brain cancers.
    Keywords:  blood-brain barrier; carbon dots; central nervous system; imaging; therapy
    DOI:  https://doi.org/10.7150/thno.130380
  39. Assay Drug Dev Technol. 2026 Mar 10. 1540658X261429259
    A Nasal Hydrogel Combining Metformin and Curcumin for Potential Nose-to-Brain Therapy in Neurodegenerative Disorders.
    Emine Dilek Özyılmaz.
       Neurodegenerative disorders such as Alzheimer's and Parkinson's disease remain a significant therapeutic challenge due to the restrictive nature of the blood-brain barrier (BBB) and the limited efficacy of current pharmacological treatments. Intranasal administration has emerged as a promising noninvasive strategy that enables direct drug delivery to the brain by bypassing the BBB. This study aimed to design and optimize a dual-drug nasal hydrogel containing metformin hydrochloride, a hydrophilic AMP-activated protein kinase activator, and curcumin, a lipophilic antioxidant and anti-amyloid agent, and to provide synergistic neuroprotection. The formulation was prepared using carbopol as the gel matrix and characterized in terms of physicochemical stability, drug content uniformity, rheology, in vitro release, and excipient compatibility. A Box-Behnken design was used to systematically evaluate the effects of carbopol, glycerin, and curcumin concentrations on critical quality attributes. The optimized hydrogel exhibited acceptable pH, viscosity suitable for nasal administration, and sustained biphasic drug release with a cumulative 6-h release of approximately 85% for metformin and 39% for curcumin according to the Higuchi drug release model (R2 > 0.98). Collectively, these results highlight the feasibility of an integrative intranasal hydrogel platform to overcome the bioavailability challenges of both agents. The proposed system offers a patient-friendly, noninvasive approach for potential nose-to-brain therapy in neurodegenerative disorders and warrants further preclinical and in vivo investigation.
    Keywords:  hydrogel; metformin–curcumin combination; neurodegenerative disorders; nose-to-brain therapy
    DOI:  https://doi.org/10.1177/1540658X261429259
  40. Prog Neurobiol. 2026 Mar 09. pii: S0301-0082(26)00031-6. [Epub ahead of print] 102905
    Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.
    Stefano Antonucci, Guillaume Caron, Natalie Dikwella, Sruthi Sankari Krishnamurthy, Anthony Harster, Bartosz Wasicki, Hina Zarrin, Aboud Tahanis, Florian Olde Heuvel, Simon M Danner, Albert C Ludolph, Kamil Grycz, Marcin Bączyk, Daniel Zytnicki, Francesco Roselli.
      Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that Adrb2 and Adrb3 adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the electrical properties of MNs, in particular the frequency-current gain, a crucial determinant of excitability. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon β-adrenergic neuromodulation.
    Keywords:  Amyotrophic Lateral Sclerosis; G protein-coupled receptors; channelome; homeostatic regulation; in vivo intracellular electrophysiology; transcriptomics; β-adrenergic neuromodulation
    DOI:  https://doi.org/10.1016/j.pneurobio.2026.102905
  41. Int J Mol Sci. 2026 Feb 25. pii: 2168. [Epub ahead of print]27(5):
    Impact of the Combination of Epigallocatechin Gallate and Ellagic Acid Supplemented with Ketone Bodies on Energetic Restoration of Mitochondrial Dysfunction and Metabolic Inefficiencies in Patients with Multiple Sclerosis: A Review.
    Jose Enrique de la Rubia Ortí, Alba Roig-Soriano, Sandra Carrera-Juliá, Alejandra Castelló-Guillen, Marisa Machado, Rocío García-Villalba, Jorge Alarcón-Jiménez, Nieves de Bernardo, María Benlloch.
      Multiple sclerosis (MS) is characterized by progressive mitochondrial dysfunction affecting complexes I, III, and IV of the electron transport chain, contributing to axonal energy failure and neurodegeneration. This review examines the potential of combining β-hydroxybutyrate (βHB), epigallocatechin-3-gallate (EGCG), and ellagic acid (EA) as a multi-target therapeutic strategy to restore mitochondrial function in patients with MS. Experimental and clinical studies demonstrate that each compound exerts complementary mechanisms. Ketone bodies provide an alternative energy substrate and restore complex I activity via sirtuin-dependent pathways. EGCG acts predominantly at the peripheral level by reducing systemic inflammation and oxidative stress. EA-derived urolithins effectively cross the blood-brain barrier to directly enhance mitochondrial biogenesis and respiratory chain function in the central nervous system. Clinical trials have reported improvements in fatigue, cognition, mood, and muscle function following supplementation with these compounds. The convergence of their actions on energy restoration, reactive oxygen species reduction, and epigenetic modulation of protective pathways suggests their synergistic potential. Optimized delivery strategies, including exogenous ketone salts, liposomal EGCG, and microencapsulated EA, may overcome bioavailability limitations and interindividual variability in the gut microbiota metabolism.
    Keywords:  ellagic acid; epigallocatechin gallate; ketone bodies; multiple sclerosis
    DOI:  https://doi.org/10.3390/ijms27052168
  42. Prog Neuropsychopharmacol Biol Psychiatry. 2026 Mar 06. pii: S0278-5846(26)00056-4. [Epub ahead of print]146 111660
    Elucidating the molecular targets in Alzheimer's disease: Advances and therapeutic implications.
    Urvashi Soni, Rohini Pujari.
      Alzheimer's disease (AD), the most prevalent form of dementia, is intrinsically linked to the biological processes of ageing, which serve as its greatest risk factor. As global life expectancy rises, age-associated neurodegenerative disorders like AD impose an escalating burden on public health systems and economies. Ageing is accompanied by a complex interplay of cellular and molecular alterations, including oxidative stress, mitochondrial dysfunction, impaired proteostasis, chronic neuroinflammation, and epigenetic drift, all of which converge to disrupt neuronal integrity and function. In AD, these ageing-related mechanisms accelerate pathological hallmarks such as amyloid-β plaque deposition, tau hyperphosphorylation, synaptic loss, and neurodegeneration. Recent advances in molecular neuroscience have unveiled a spectrum of novel targets involved in the pathogenesis of AD, ranging from secretases and tau kinases to microglial receptors and mitochondrial bioenergetic regulators. This review elucidates the therapeutic strategies aimed at modulating these targets, including the use of small-molecule inhibitors, monoclonal antibodies, gene therapies, and epigenetic modifiers. Additionally, the impact of blood-brain barrier integrity on neuronal energy metabolism and its correlation with AD pathology is examined. The findings underscore the importance of interdisciplinary approaches in AD research, highlighting future directions and challenges in developing effective treatments. By advancing our understanding of the molecular nexus of AD, this work aims to contribute to the ongoing efforts to mitigate the effects of this debilitating condition and improve patient outcomes.
    Keywords:  Ageing; Alzheimer's disease; Molecular targets; Neurodegeneration; Neuroinflammation; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.pnpbp.2026.111660
  43. Biosens Bioelectron. 2026 Mar 02. pii: S0956-5663(26)00199-5. [Epub ahead of print]303 118567
    An electrochemical enzyme-linked immunosorbent assay for interleukin 18 quantification in 3D skin models derived from ALS patients.
    Nicola Furlan, Ugo D'Amora, Ines Fasolino, Alessandro Silvestri, Chiara Zanardi.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that currently lacks validated molecular biomarkers for early diagnosis and prognosis, severely delaying personalized care. Interleukin 18 (IL-18), a proinflammatory cytokine linked to NLRP-3 inflammasome activation, has emerged as a promising biomarker for ALS. However, traditional colorimetric Enzyme-Linked Immunosorbent Assays (ELISAs) lack the sensitivity to distinguish IL-18 levels between Fast- and Slow-progressing ALS patients. To overcome this, we developed a highly sensitive electrochemical ELISA (e-ELISA) test by systematically optimizing key parameters, including the capture antibody immobilization strategy, the electrochemical mediator, and reagent concentrations. We then applied the optimized e-ELISA protocol to quantify IL-18 in 3D innervated skin models constructed using 3D-printed methacrylated hyaluronic acid (MeHA) and electrospun polylactic acid (PLLA) fibers, and colonized with patient-derived fibroblasts and neuronal cells. Reaching a limit of detection of 1.77 pg✕mL-1, the e-ELISA not only differentiated ALS models from the healthy control but, most critically, distinguished between a Fast- and a Slow-progressing ALS models based on significantly different IL-18 concentrations. By discriminating IL-18 levels in biologically representative models, this work validates the developed high-performance e-ELISA for personalized clinical use, providing a foundation for the design of portable diagnostic devices.
    Keywords:  3D skin model; Amyotrophic lateral sclerosis (ALS); Electrochemical Enzyme-Linked Immunosorbent Assays (e-ELISA); Interleukin 18 (IL-18)
    DOI:  https://doi.org/10.1016/j.bios.2026.118567
  44. Neuroscience. 2026 Mar 06. pii: S0306-4522(26)00158-2. [Epub ahead of print]601 121-135
    Effects of different exercise modalities on four major neurodegenerative diseases and their molecular mechanisms.
    Shuo Wang, Yuqing Wei, Yongbiao Li, Hong Qing, Yan Yan, Yong Cheng.
      Neurodegenerative diseases are marked by progressive neuronal damage and currently lack a cure. Recently, exercise has emerged as a promising non-pharmacological approach to potentially slow disease progression and enhance cognitive function. This narrative review summarizes the effects of various exercise modalities-including aerobic exercise, resistance training, and balance training-on four major neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, and spinocerebellar ataxia), as well as their underlying molecular mechanisms. Evidence from existing studies suggests that aerobic exercise activates the AMPK/PGC-1α signaling pathway, promoting mitochondrial biogenesis and supporting astrocyte function, which in turn reduces β-amyloid accumulation and neuroinflammation. Resistance and balance training primarily improve muscle strength and coordination, leading to better motor performance and quality of life. Additionally, exercise modulates the release of neurotrophic factors, enhancing synaptic plasticity and neurogenesis. The review also discusses optimal exercise protocols tailored to specific diseases, providing a foundation for clinical application and future research. Moving forward, studies should focus on personalized exercise regimens and long-term outcomes to maximize the benefits of non-pharmacological interventions in neurodegenerative diseases.
    Keywords:  Aerobic exercise; Cognitive function; Neurodegenerative diseases; Resistance training
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.03.001
  45. Int J Mol Sci. 2026 Mar 03. pii: 2370. [Epub ahead of print]27(5):
    From Polyphenols to Prodrugs: Bridging the Blood-Brain Barrier with Nanomedicine and Neurotherapeutics.
    Masaru Tanaka, Adriano Cressoni Araujo, Vítor Engrácia Valenti, Elen Landgraf Guiguer, Vitor Cavallari Strozze Catharin, Cristiano Machado Gualhardi, Eliana de Souza Bastos Mazuqueli Pereira, Ricardo de Alvares Goulart, Rafael Santos de Argolo Haber, Atonelly Cassio Alves de Carvalho, Sandra Maria Barbalho.
      Central nervous system disorders drive disability, yet many neuroactive candidates fail because the brain is a hard compartment to dose. Plant-derived molecules spanning polyphenols, alkaloids, terpenoids, and cannabinoids are attractive because their pleiotropic actions can engage oxidative stress, neuroinflammation, and circuit dysfunction. In practice, the blood-brain barrier (BBB) restricts most native phytochemicals through tight-junction selectivity, rapid metabolism, low solubility, and transporter-mediated efflux. Key gaps include poor standardization of exposure metrics, limited human-relevant BBB models, and few head-to-head studies that compare delivery platforms on the same payload and outcome. This review tackles the mismatch between mechanistic promise and reliable brain exposure that stalls translation. The objectives are to link phytochemical liabilities to enabling strategies in nanomedicine, alternative routes, and transporter-targeted prodrugs, and to propose decision-grade endpoints for translation. We synthesize evidence on BBB transport logic, nanocarrier families, targeting ligands, intranasal delivery, focused ultrasound-mediated opening, and prodrug approaches that hijack influx transporters, while foregrounding safety and chemistry, manufacturing, and controls (CMC) constraints. Here we highlight that effective neurotherapeutics emerge when chemistry, carrier, route, and measurement are co-designed rather than optimized in isolation. This framework can guide platform selection, de-risk first in-human studies, and sharpen trial endpoints. More broadly, it offers a transferable playbook for barrier-limited drug development across neurology, psychiatry, and oncology.
    Keywords:  blood–brain barrier (BBB); central nervous system diseases (CNS); drug delivery systems; intranasal; kynurenines; nanomedicine; nanoparticles; phytochemicals; prodrugs; transferrin receptor; ultrasonic therapy
    DOI:  https://doi.org/10.3390/ijms27052370
  46. Cells. 2026 Feb 27. pii: 417. [Epub ahead of print]15(5):
    Claudins in Retinal Disease: Beyond Barrier Integrity to Signaling and Therapy.
    Mohamed S Selim, S Priya Narayanan, Payaningal R Somanath.
      The blood-retinal barrier (BRB) maintains neurovascular homeostasis by regulating solute and ion exchange between the retina and circulation. This selectivity depends on tight junctions (TJs), with claudin (Cldn) proteins forming the core structure that defines paracellular permeability. Distinct Cldn isoforms show cell-specific expression, with Cldn-5 predominating in the endothelial cells of the inner BRB and Cldn-19 is the signature Cldn in the retinal pigment epithelium forming the outer BRB. Disruption of these isoforms contributes to vascular leakage, inflammation, and neuronal loss across various ocular diseases. Cldn function in vascular homeostasis is multifaceted; barrier dysfunction does not always result from Cldn loss, as excessive expression or mislocalization, particularly of Cldn-5, can also impair BRB integrity. Cldns act as dynamic signaling hubs that respond to metabolic, oxidative, and mechanical stress and are regulated through VEGF, Wnt/β-catenin, and RhoA/ROCK pathways. This review summarizes current understanding of Cldn biology in retinal vascular regulation and highlights emerging therapeutic strategies aimed at stabilizing Cldn expression and junctional localization. Small molecules and blocking antibodies that enhance localization or prevent degradation are redefining barrier repair. Key questions remain regarding isoform specificity, inter-barrier communication, and systemic safety. Integrative omics and spatial imaging may reveal disease-specific Cldn signatures and guide molecular restoration of BRB integrity.
    Keywords:  blood–retinal barrier; claudins; endothelial permeability; retinal pigment epithelium; retinopathy; tight junctions
    DOI:  https://doi.org/10.3390/cells15050417
  47. Neuron. 2026 Mar 11. pii: S0896-6273(26)00086-3. [Epub ahead of print]
    Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.
    Zhilong Zheng, Wangju Yang, Zhen Chen, Panpan Chen, Mengdan Tao, Shengda Wang, Bowei Cui, Zeyue Yang, Yanqing Yan, Xiao Han, Yongjie Zhang, Zijian Ren, Xiaoxin Yan, Yueqing Jiang, Jing Wang, Tingyou Li, Yan Liu, Xing Guo.
      Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.
    Keywords:  ALS; NMJ; PGAM5; VCP; amyotrophic lateral sclerosis; mitochondrial integrated stress response; mitochondrial phosphatase phosphoglycerate mutase 5; mtISR; neuromuscular junction; valosin-containing protein
    DOI:  https://doi.org/10.1016/j.neuron.2026.02.003
  48. Ann Indian Acad Neurol. 2026 Mar 12.
    An Unusual Presentation of Juvenile Amyotrophic Lateral Sclerosis with Superoxide Dismutase 1 Mutation: Subacute Bulbar Palsy With Asymmetric Limb Weakness.
    Venkataraman Viswanathan, Guna Madhuri, Kumaresan Ganapathi, Nirmal Kumar.
      
    DOI:  https://doi.org/10.4103/aian.aian_1088_25
  49. Neuropeptides. 2026 Mar 05. pii: S0143-4179(26)00021-1. [Epub ahead of print]117 102605
    Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical.
    Esther Louise Sabban, Arax Tanelian.
      Compelling evidence from a variety of approaches attributes manifold benefits to NPY in the brain. NPY can reduce stress, depressive symptoms, pain, neuroinflammation, seizures, and is implicated in attenuating alcohol use disorder and neurodegenerative diseases, such as Alzheimer's, Machado-Joseph and Huntington Disease. NPY enhances immune regulation, neuro-proliferation, memory and cognition. However, its therapeutic potential has not yet been realized. Intranasal nose to brain (N2B) delivery is a non-invasive approach that can provide high bioavailability with limited side effects. Here we discuss therapeutic opportunities and challenges of N2B administration of NPY and related agonists. Preclinical N2B administration of NPY, either alone or with other compounds, to experimental animals has been very successful. For example, a single NPY intranasal infusion to male rats was able to prevent, as well as reverse, many behavioral impairments triggered by Single Prolonged Stress model for PTSD. Females were found to require higher doses of NPY, or pretreatment with a DPPIV inhibitor, to provide resilience. In humans, limited studies found that intranasal administration of NPY in saline was well tolerated and showed promise for PTSD or depression at highest dose administered. However, saline should be avoided in favor of water for aqueous delivery, and each sex should be analyzed separately. Overall, these findings call for further work to enhance N2B delivery of NPY or selective agonists to human brain to harness NPY's exciting therapeutic potential.
    Keywords:  Clinical; Intranasal; Neuropeptide Y; Neuroprotection; Nose to brain; Post traumatic stress disorder; Preclinical; Resilience; Sex differences; Stress
    DOI:  https://doi.org/10.1016/j.npep.2026.102605
  50. PLoS One. 2026 ;21(3): e0331275
    Comparison of neonatal systemic and intracerebroventricular AAV9 gene therapy delivery demonstrating improved behavioral and phenotypic outcomes in a mouse model of Niemann-Pick disease, type C1.
    Benjamin E Epstein, Gabrielle M Soden, Arturo A Incao, Avani Mylvara, Jonathan Flynn, Fatih Ozsolak, William J Pavan.
      Niemann-Pick disease, type C (NPC), is an inherited fatal lysosomal storage disorder caused by a mutation in the NPC1 or NPC2 genes and characterized by impaired lysosomal cholesterol export. Previous studies have demonstrated that delivery of the NPC1 gene to the central nervous system (CNS) via an adeno-associated virus (AAV) can substantially improve lifespan and mitigate signs of disease in Npc1-deficient mouse models of NPC. To determine the optimal parameters for an efficacious AAV-based gene therapy for NPC, we measured the survival and disease phenotypes of mice treated systemically as neonates or at weaning age, along with neonatal mice treated via intracerebroventricular (ICV) delivery, with a construct containing either a ubiquitous truncated EF1α promoter or a truncated Mecp2 promoter. While all constructs and delivery methods resulted in improvement compared with baseline, mice treated as neonates survived significantly longer and experienced slower disease progression compared with those treated systemically at weaning age. Systemic delivery to neonates was capable of increasing survival and phenotypic improvement comparable to that of ICV delivery, and neonatal systemic and ICV delivery were both similarly capable of near-total Purkinje cell rescue. We also found no difference between a ubiquitous EF1α-derived promoter and an Mecp2-derived promoter. Ultimately, early treatment with maximal access to the CNS, whether via systemic or direct CNS delivery, is key to the efficacy of gene therapy in treating NPC.
    DOI:  https://doi.org/10.1371/journal.pone.0331275
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