bims-axbals 2026-08-30 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–08–30
twenty-two papers selected by
TJ Krzystek

Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.
Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.
Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.
Huntingtin, signaling endosomes and neuronal survival in health and Huntington disease.
The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.
A Contemporary Pathomechanistic Nosology of Inherited Lysosomal Disorders.
TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.
Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.
Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder.
ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?
Functional Activity of TDP-43: A Direct Biomarker for ALS.
Detection of TDP-43 Proteinopathies in Brain and Cerebrospinal Fluid Using Seed Amplification Assay.
The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.
M6PR/IGF2R double-knockout supplies therapeutic sources for mucolipidosis II and Niemann-Pick C2.
PTEN regulates microtubule polymerization via mTORC2, but not mTORC1, in peripheral sensory neurons.
Neurodevelopmental miR-135a-1-3p and miR-135b-3p promote long-distance axon regeneration after injury in the central visual pathway.
G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.
Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.
Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons.
Circular RNAs in Neurons: From Transport to Function.
An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis.

Biology (Basel). 2026 Aug 07. pii: 1334. [Epub ahead of print]15(16):

Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.

Maria Ciuro, Chantal Rovetto, Angela A Sirna, Salvatore Giunta, Giampiero Leanza, Rosario Gulino.

  Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1G93A mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS.

Keywords:  Mdivi-1; SOD1G93A mouse model; TAR DNA-binding protein 43; amyotrophic lateral sclerosis; dynamin-related protein 1; mitochondrial dynamics; motor neurons; physiology; skeletal muscle atrophy; synaptic plasticity

DOI:  https://doi.org/10.3390/biology15161334
Nat Biomed Eng. 2026 Aug 26.

Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.

Huishan Guo, Alexandre Savard, Charlotte Manser, Kallol Dutta, James A Taylor, Maxime W C Rousseaux, Silvia Pozzi, Jean-Pierre Julien, Stephen Baird, Derrick Gibbings.

In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43G298S iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43ΔNLS mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.

DOI: https://doi.org/10.1038/s41551-026-01774-9
Neurobiol Dis. 2026 Aug 24. pii: S0969-9961(26)00327-X. [Epub ahead of print] 107582

Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.

Nicolette Heinsinger, Yi Wang, Steve Grauer, Zuo Zhang, Jacky Wong, Vladimir Simov, Marina Bukhtiyarova, Xi Ai, Craig Parish, Rebecca Meier Klein, Jason Uslaner, Sean Smith, Yuan Tian.

  ATXN2 is associated with an increased risk of Amyotrophic Lateral Sclerosis (ALS), while down-regulation of ATXN2 has been shown to mitigate TDP-43 proteinopathy in ALS models. In this study, we demonstrated that Ataxin-2 protein levels were upregulated in rNLS8 mice following doxycycline withdrawal, which coincided with TDP-43 overexpression, phosphorylation, and aggregation. To reduce Ataxin-2 protein levels, we explored the approach of splicing modulation at the RNA level. Through bioinformatical analysis, we identified an alternative 5' splicing site of ATXN2 in intron 8. This alternative splicing results in an additional 47 base pairs at the 3' end after Exon 8. The insertion of the extra nucleotides causes a frameshift that leads to reduced mRNA production and, consequently, protein levels. Following the discovery of this alternative splicing site, we conducted an antisense oligonucleotide (ASO) micro-walk to screen ASOs targeting this region. We identified ASOs that specifically modulate this splicing, including those that either enhance or inhibit alternative splicing. We validated that the ASOs that promote alternative splicing and reduce constitutive splicing can lower Ataxin-2 protein levels, which in turn decreases TDP-43 aggregation and stress granule formation in a cell-based model of TDP-43 toxicity. Furthermore, we confirmed that reducing Ataxin-2 levels via previously validated ASO delivery ameliorated TDP-43 pathology in rNLS8 mice. The discovery of ATXN2 alternative splicing, along with the confirmation of splicing modulation using ASOs in human cell-based assays, provides evidence for a proof-of-principle strategy to modulate Ataxin-2 protein levels for the treatment of ALS.

Keywords:  ALS; ASO splicing modulation; ATXN2; Alternative splicing; Constitutive splicing; Stress granules; TDP-43; iPSC-derived neurons; qPCR; rNLS8; ∆NLS-TDP43

DOI:  https://doi.org/10.1016/j.nbd.2026.107582
J Huntingtons Dis. 2026 Aug 24. 18796397261480227

Huntingtin, signaling endosomes and neuronal survival in health and Huntington disease.

Myriam Saliba, Frédéric Saudou, Chiara Scaramuzzino.

  The axonal transport of organelles mediates several functions throughout the lifespan of neurons. Over the past years, the role of endosomes, a specific type of trafficking organelle, has been extensively investigated for their increasing relevance during development, maturation and maintenance of neuronal networks. Endosome formation results from membrane invagination events driven by endocytic pathways. Following their formation, endosomes undergo maturation steps, and their fate is determined by the recruitment of specific cytosolic proteins to their membrane. Early endosomes may be recycled, signal in the distal compartments (signaling endosomes) or undergo fusion with autophagosomes (amphisomes), thus entering the degradation pathways together with lysosomes. Altogether, these processes regulate plasma membrane equilibrium at the synapse, further recycling and degradation of dysfunctional or toxic proteins, and promote the distribution of fundamental signals far from the synapses. Many of these pathways involve huntingtin (HTT) functions and are impaired in Huntington disease (HD). The past years have shed light on newly identified mechanisms involving the endocytic machinery with special attention being paid to long-range signaling endosome trafficking in axons. In this review, we will summarize the recent advancements and discuss the potential implications of therapeutic approaches to rescue these processes in the context of HD.

Keywords:  Huntingtin; Huntington disease; neurotrophins; signaling endosomes

DOI:  https://doi.org/10.1177/18796397261480227
Biomolecules. 2026 Aug 19. pii: 1208. [Epub ahead of print]16(8):

The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.

Zhenzhen Wang, Yuhan Fu, Siqi Li, Yan Zhang, Tao Sun, Nan Miao.

  Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in motor dysfunction. Emerging evidence underscores the significant roles of long non-coding RNAs (lncRNAs) in motor neuron development and disease. However, only a few have been experimentally confirmed as true ceRNA regulators, highlighting the need to differentiate validated mechanisms from mere associations or predictions. This review summarizes the regulatory roles of lncRNA-associated ceRNA networks in motor neuron development, evaluates the evidence for their involvement in MNDs, and explores their potential impact on disease progression. It also addresses current challenges, knowledge gaps, and future research directions for understanding ceRNA-mediated mechanisms and developing therapeutic strategies for MNDs.

Keywords:  ALS; MND; MS; SMA; ceRNA network; lncRNA

DOI:  https://doi.org/10.3390/biom16081208
J Inherit Metab Dis. 2026 Sep;49(5): e70245

A Contemporary Pathomechanistic Nosology of Inherited Lysosomal Disorders.

Eamon P McCarron, Nenad Blau, Emily R Eden, Frances M Platt, Johannes M Aerts, Simon A Jones, Carlos R Ferreira, Karolina M Stepien.

  Lysosomal disorders (LDs) have traditionally been defined by intra-lysosomal substrate accumulation resulting from deficiencies of lysosomal enzymes or associated proteins. Advances in lysosomal biology have demonstrated that lysosomes function as central regulators of cellular signalling, membrane trafficking, autophagy, nutrient sensing, organelle communication and cellular homeostasis, expanding the spectrum of inherited disorders associated with lysosomal dysfunction beyond classical storage phenotypes. We developed a contemporary pathomechanistic nosology of inherited LDs through expert curation and targeted review of databases and published literature. Disorders were included when pathogenic variants resulted in lysosomal dysfunction as a major disease mechanism through defects affecting lysosomal degradation, membrane function, intracellular trafficking, biogenesis, autophagy-lysosome pathways or lysosome-related organelles. A total of 108 inherited lysosomal disorders caused by defects in 102 genes were identified and organised into 11 major disease categories. Neurologic and eye involvement were the most frequently affected organ-system categories, occurring in 80.6% and 68.5% of disorders, respectively. Digestive (including hepatosplenomegaly), dysmorphic, skeletal and haematological involvement occurred in 48.1%, 45.4%, 40.7% and 38.9% of disorders, respectively. Distinct phenotypic signatures were observed across disease categories despite substantial mechanistic overlap involving impaired autophagy, vesicular trafficking, lysosomal stress and altered organelle homeostasis. This proposed nosology extends disease classification beyond substrate accumulation alone and provides a biologically informed framework for disease classification, genomic interpretation, biomarker development, patient stratification and the development of mechanism-based therapies.

Keywords:  autophagy; disease classification; endolysosomal pathway; inherited lysosomal disorders; inherited metabolic disorders; lysosomal storage disorders; lysosome; nosology

DOI:  https://doi.org/10.1002/jimd.70245
JAMA Neurol. 2026 Aug 24.

TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.

Michael Benatar, Sami Barmada, Gregory A Jicha, Clotilde Lagier-Tourenne, Jenna Gregory, Ammar Al-Chalabi, Bradley F Boeve, Clifford R Jack, William W Seeley, Nicholas J Maragakis, Joanne Wuu, Zane Zeier, Chiadi Onyike, Joe Lewcock, Collin Hovinga, Paymaan Jafar-Nejad, Olga Uspenskaya, Adam Simmons, Susan E Browne, Jonathan Rohrer, Leonard Petrucelli, Jacquelyn Shapiro, Deb Scharper, Adam Boxer, Lyle W Ostrow, Adam M Staffaroni, Penny Dacks, Martin R Turner, Kuldip D Dave, Martina de Majo, Laura Mitic, Stephanie Fradette, Samantha Budd Haeberlein, Tanya Simuni, Billy Dunn, Corey T McMillan, Edward B Lee.

Importance: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.
Observations: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.
Conclusions and Relevance: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.

DOI: https://doi.org/10.1001/jamaneurol.2026.2812
Stem Cell Res. 2026 Aug 22. pii: S1873-5061(26)00181-9. [Epub ahead of print]95 104085

Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.

Dide Wu, Ana Kojic, Jay P Ross, Dong Li, Parker Walther, Neelam Goyal, Jacinda Sampson, Joseph C Wu.

The GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene constitutes the leading genetic driver of amyotrophic lateral sclerosis (ALS). This fatal neurodegenerative disorder is characterized by the systematic loss of both the upper and lower motor neurons across both the central and peripheral nervous systems. This work describes the successful reprogramming of two human induced pluripotent stem cell (iPSC) lines originating from two independent ALS patients, both of whom carry a C9orf72 HRE mutation. Validation of the two established iPSC lines confirmed the expression of pluripotency markers, normal karyotypes, and successful trilineage differentiation. Consequently, these lines provide a robust in vitro platform to model ALS and study C9orf72-mediated disease mechanisms.

DOI: https://doi.org/10.1016/j.scr.2026.104085
Nat Commun. 2026 Jul 28. pii: 9165. [Epub ahead of print]17(1):

Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.

Chuyu Chen, Qianzi He, Giulia Tombesi, Eve Napier, Matthew Jaconelli, Oscar Andrés Moreno-Ramos, Hannah Serio, Yahaira Naaldijk, Vanessa Promes, Amanda Schneeweis, Kaitlyn Quinn, Christopher Nasios, Elisa Greggio, Yevgenia Kozorovitskiy, Daniel Arango, Amir R Khan, Dario R Alessi, Daniel A Dombeck, Sabine Hilfiker, Rajeshwar Awatramani, Loukia Parisiadou.

Parkinson's disease (PD) is defined pathologically by loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). Yet synaptic dysfunction emerges much earlier, making it essential to define the mechanisms that drive early nigrostriatal deregulation. In the SNc, molecularly distinct dopamine neuron subtypes show differential susceptibility to PD. Here, we used intersectional genetic mouse models to determine how the PD-linked kinase LRRK2 affects vulnerable dopamine subtypes. Immunofluorescence and proximity-labeling proteomics revealed enriched LRRK2 expression in vulnerable dopamine neuron subclusters. High-resolution imaging showed that pathogenic LRRK2 disrupts presynaptic release-site organization in vulnerable dopamine axons, leading to reduced spontaneous and evoked striatal dopamine release in vivo. Proteomic analyses further showed that mutant LRRK2 increases phosphorylation of RAB3 proteins, impairing their interaction with the active-zone effectors RIM1 and RIM2. Together, these findings highlight a subtype-specific, cell-autonomous mechanism by which pathogenic LRRK2 impairs PD-vulnerable nigrostriatal synapses and provide a framework for therapeutic strategies targeting early synaptic deficits in PD.

DOI: https://doi.org/10.1038/s41467-026-75194-3
Sci Transl Med. 2026 Aug 26. 18(864): eady7616

A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder.

Jimin Han, Nathaniel Foley, Sonal Dalvi, Janet A H Tang, Fesahat Emira Dogrul, Amit Chatterjee, Lal Krishan Kumar, Chad A Galloway, Ajay Kumar Singh, Leah M Stein, Yashoda Subedi, Kevin C Ling, Alison Heffer, Xingxuan He, Vamsi K Gullapalli, Brent A Johnson, Richard T Libby, Danielle S W Benoit, Anthony L Cook, Vera L Bonilha, Edward H Schuchman, Jennifer J Hunter, Ruchira Singh.

Disruption of the photoreceptor-retinal pigment epithelium (RPE) interface, with loss of photoreceptor outer segments (POSs) in the retina, is a pathological hallmark of several neurodegenerative and retinal diseases, including lysosomal storage disorders like juvenile neuronal ceroid lipofuscinosis (CLN3) disease. However, in vitro stem cell models that enable investigation of the photoreceptor-RPE interface are lacking. Here, we developed a 3D human pluripotent stem cell-derived retina organoid-RPE (hPSC-RO-RPE) model to investigate the photoreceptor-RPE interface in healthy and diseased tissues. Using this 3D hPSC-RO-RPE retina model, we showed that the most common disease-causing CLN3 mutation (CLN3Δex7-8) leads to reduced levels of acid ceramidase (AC), sphingosine 1 phosphate, and POS loss. Furthermore, by analyzing control versus CLN3 mutant (CLN3Δex7-8) hPSC-derived RPE monoculture and hPSC-RO-RPE model, (i) we identified a pathogenic role of AC-mediated lysosomal sphingolipid metabolism in promoting CLN3 disease pathobiology, and (ii) we showed a cell autonomous role of the RPE dysfunction in promoting POS loss/retina degeneration in CLN3 disease. We validated the molecular and structural changes observed in the CLN3Δex7-8 hPSC-RO-RPE model in the CLN3 miniswine model (CLN3Δex7-8) and donor eyes from two patients with CLN3 disease. High-resolution retinal imaging of the living eye in two patients with CLN3 disease suggested decreased RPE autofluorescence in early-stage CLN3 disease. Treatment with recombinant human acid ceramidase (rhAC) ameliorated photoreceptor degeneration in both the CLN3 disease RO-RPE model and CLN3 miniswine eyes. These findings suggest that rhAC could be a therapeutic approach for retinal degeneration in CLN3 disease.

DOI: https://doi.org/10.1126/scitranslmed.ady7616
Biomolecules. 2026 Aug 01. pii: 1126. [Epub ahead of print]16(8):

ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?

Hiroshi Mitsumoto, Hélène Blasco, Philippe Corcia, Vincenzo Silani.

  Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.

Keywords:  ALS; MND; amyotrophic lateral sclerosis; bioenergetics; frontotemporal systemic disease; hypothalamus; metabolic disease; mitochondria; mitochondrial associated membrane (MAM); motor neuron disease; multisystem involvement

DOI:  https://doi.org/10.3390/biom16081126
Biosensors (Basel). 2026 Aug 17. pii: 446. [Epub ahead of print]16(8):

Functional Activity of TDP-43: A Direct Biomarker for ALS.

Kirti Shila Sonkar, Vito Levi D'Ancona, Jade Cramp, Hannah Shilling, Ellie Giles, Tyler Howell-Bray, Becky Fillingham, Merit E Cudkowicz, Avindra Nath, Jeffrey D Rothstein, Robert Bowser, Barbara Borroni, James D Berry, Ghazaleh Sadri-Vakili, Emanuele Buratti, Ian P Thrippleton.

  TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (302 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular release of probe-competent TDP-43 species during cell death and exosomal shedding, rather than restored intracellular nuclear splicing function. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies.

Keywords:  RNA-binding function; TDP-43; amyotrophic lateral sclerosis; functional proteomics; hTR-FRET; serum biomarker

DOI:  https://doi.org/10.3390/bios16080446
Curr Issues Mol Biol. 2026 Aug 13. pii: 824. [Epub ahead of print]48(8):

Detection of TDP-43 Proteinopathies in Brain and Cerebrospinal Fluid Using Seed Amplification Assay.

Katsuya Satoh, Mika Inada Shimamura, Takeshi Fujimoto, Michio Kitayama, Akio Akagi, Yasushi Iwasaki, Yuu Satoh, Katsuhiro Ichinose, Akira Satoh, Ikuko Takahashi Iwata, Ichiro Yabe.

  Misfolded TAR DNA-binding protein 43 (TDP-43) is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), have shown promise in detecting misfolded TDP-43 in cerebrospinal fluid (CSF) and olfactory mucosa, technically accessible methodologies are urgently required for widespread clinical application. We developed a streamlined, non-immunoprecipitation-based TDP-43 RT-QuIC assay to assess seeding activity in brain tissue and CSF. We evaluated its diagnostic performance using CSF from patients with TDP-43 proteinopathies and control subjects, and further examined its association with neurofilament light chain (NfL) and tau-related biomarkers. In CSF analysis, the assay demonstrated positive seeding activity in 70% (21/30) of patients with ALS and dementia, 50% (5/10) of patients with FTLD, and 40% (8/20) of patients with ALS alone. The assay exhibited excellent specificity, yielding negative results in >99% (199/200) of control samples, including those with autoimmune or electrophysiological abnormalities. Furthermore, CSF analysis demonstrated significantly higher NfL levels in TDP-43 SAA-positive cases compared to SAA-negative cases (p < 0.0008). The highest NfL concentrations were observed in the SAA-positive ALS with dementia and ALS cohorts, contrasting with lower levels in FTLD. Tau-related biomarkers exhibited no significant differences between the groups. Our streamlined, non-immunoprecipitation TDP-43 RT-QuIC assay provides highly specific detection of pathological TDP-43 seeding activity. While the assay detects the underlying TDP-43 proteinopathy rather than distinguishing between ALS and FTLD clinical phenotypes, its technical simplicity and combined utility with NfL measurements offer a robust, scalable framework for biomarker development. This approach provides a practical foundation for future multi-center validation and international standardization efforts.

Keywords:  TDP-43; amyotrophic lateral sclerosis; biomarkers; frontotemporal lobar degeneration; seeding amplification assay

DOI:  https://doi.org/10.3390/cimb48080824
Int J Cell Biol. 2026 ;2026 3022967

The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.

Fiona C Dresel, Martin Michaelis, Campbell W Gourlay.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota-derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS-related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1G85R. Mechanistically, NaB recapitulated the effects of the pan-HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1A4V, Sod1G85R or Sod1G37R in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.

DOI: https://doi.org/10.1155/ijcb/3022967
J Biol Chem. 2026 Aug 28. pii: S0021-9258(26)02383-5. [Epub ahead of print] 113511

M6PR/IGF2R double-knockout supplies therapeutic sources for mucolipidosis II and Niemann-Pick C2.

Toshiharu Fujita, Seigo Terawaki, Takahito Moriwaki, Takanobu Otomo.

  Lysosomal storage disorders (LSDs) are intractable rare diseases caused by lysosomal dysfunction due mainly to defects in lysosomal enzyme genes. For many lysosomal enzymes to be transported correctly into lysosomes, their mannose-6-phosphate (M6P) labeling by GlcNAc-1 phosphotransferase (GNPT) is crucial. M6P-modified lysosomal enzymes are captured by M6P receptors and transported to lysosomes. The M6P-dependent pathway is utilized not only for newly synthesized lysosomal enzymes but also for the intracellular transport of exogenously administered lysosomal enzymes to lysosomes. In this study, we performed gene knockouts targeting the M6PR and IGF2R genes, which encode the M6P receptors. Cells with a double knockout of these genes secrete M6P-modified proteins into the culture supernatant (dKO sup), and we investigated its potential for therapeutic application. I-cell disease (mucolipidosis II, ML-II) arises from GNPT deficiency and is a disorder in which dozens of lysosomal enzymes are deficient within the cell. Treating ML II cells with the dKO sup restored lysosomal enzyme activity, reduced inclusion bodies, and improved autophagic function. ML II patient-derived fibroblasts exhibited increased lysosomal enzyme activities, normalized morphology, and improved cryo-viability with the treatment. NPC2 protein is not a lysosomal enzyme but functions cooperatively with NPC1 protein to mediate cholesterol transport in lysosomes. NPC2 deficiency causes Niemann-Pick disease type C2, and the dKO sup restored the cellular function of the disease by supplementing the NPC2 protein. These results indicate that M6PR/IGF2R double-deficient cells provide a simple platform for supplying M6P-modified proteins that can be applied to the treatment of a broad range of LSDs.

Keywords:  GlcNAc-1-phosphotransferase; I-cell disease; Niemann-Pick C2; enzyme replacement therapy; lysosomal storage disorder; lysosome; mannose 6-phosphate; mucolipidosis II

DOI:  https://doi.org/10.1016/j.jbc.2026.113511
eNeuro. 2026 Aug 25. pii: ENEURO.0116-26.2026. [Epub ahead of print]

PTEN regulates microtubule polymerization via mTORC2, but not mTORC1, in peripheral sensory neurons.

Simone Evans, Julia Reglewski, Haley Rose, Cara Lewis, Anika Nayak, Cole Minsky, Evan McNeil, Brizha Knowles, Wei Wang, Meijie Li, Bryan W Luikart, Jennifer Hong.

Peripheral neuropathy affects over 18 million adults in the U.S. (Hicks et al 2021), but therapeutic outcomes are poor due to a lack of regenerative treatments. Development of novel, disease-modifying therapies is hindered by poor understanding of the mechanisms promoting axonal regeneration in peripheral neurons. Pten is a strong negative regulator of cell growth, and Pten-KO drives axonal regeneration in various neuronal subtypes potentially via downstream regulation of stability of the microtubule (MT) cytoskeleton, a vital component of axonal growth. While Pten-KO accelerates MT polymerization rates in the axonal growth cone, it remains unknown whether this action is dependent on mTORC1 or mTORC2 signaling, and whether regeneration under Pten-KO is dependent on MT activation. Here, we perform in vitro codeletions of either Raptor (mTORC1) or Rictor (mTORC2) alongside Pten-KO in mouse peripheral sensory neuron cultures of either sex to isolate the effects of each pathway on the MT cytoskeleton. We use Pten-KO to increase MT polymerization and neuronal outgrowth, and then show that suppression of mTORC2, but not mTORC1, is sufficient to reduce the accelerated MT polymerization and neuronal hypertrophy to wild-type levels. These results are specific to the axonal growth cone, and MT dynamics in the proximal axon shaft are not impacted by Pten-KO, mTORC1 suppression, or mTORC2 suppression. Our results help elucidate the mechanism by which Pten regulates the MT cytoskeleton and axonal outgrowth in peripheral sensory neurons, localize where this occurs in the axon, and highlight the MT cytoskeleton as a potential molecular target for regenerative therapies.Significance statement Pten-KO promotes neuron growth, but Pten has several downstream effectors, and it is unclear which effectors drive axonal regeneration. One of these downstream targets is the microtubule cytoskeleton, which is vital for normal axonal growth and development. We demonstrate that Pten-KO increases MT polymerization rates in the growth cone, but not proximal shaft, in axons of peripheral sensory neurons. This effect is reversed by co-deletion of mTORC2, but not mTORC1, and the loss of mTORC2 primarily inhibits elongation of the distal axon, suggesting that the regulation of MT polymerization is specific to the growth cone. These results highlight MT dynamics in the axonal growth cone as a vital component of peripheral neuron regeneration and a potential therapeutic target.

DOI: https://doi.org/10.1523/ENEURO.0116-26.2026
Mol Ther Adv. 2026 Sep 10. 34(3): 201826

Neurodevelopmental miR-135a-1-3p and miR-135b-3p promote long-distance axon regeneration after injury in the central visual pathway.

Jacob H Brady, Agnieszka Lukomska, Arnav J Balaji, Clyde D'Souza, Ephraim F Trakhtenberg.

  Micro-RNAs (miRNAs) play roles in the mammalian central nervous system (CNS) development and disease but the functions of specific miRNA families' members in defined neuronal types are poorly understood. Here, we characterized the miR-135 family members in the mouse CNS retinal ganglion cell (RGC) and cortical projection neurons development, and tested whether reverting expression toward embryonic levels for the identified developmentally regulated miR-135 family members may reactivate the intrinsic axon growth capacity following axonal injury in the adult CNS. We found that two-out-of-five miR-135 family members, miR-135a-1-3p and miR-135b-3p, were developmentally downregulated, with further downregulation after axonal injury, in neurons. Importantly, RGC-targeted mimics of miR-135a-1-3p and miR-135b-3p promoted neuroprotection and axon regeneration following optic nerve injury, with axons regrowing through a segment of the central visual pathway when co-treated with an axon growth-supporting small fibronectin-based recombinant protein. Finally, transcriptomic profiling of the treated RGCs showed that genes involved in neurodevelopment/neuroprotection were embedded in the gene networks affected by the treatments. Thus, miR-135a-1-3p and miR-135b-3p are developmentally downregulated in the mammalian CNS projection neurons and present options for translation toward CNS injury treatments.

Keywords:  CNS repair; axon regeneration; miR-135; micro-RNAs; neuron gene therapy; neuroprotection; optic nerve injury; optic neuropathy; retinal ganglion cell

DOI:  https://doi.org/10.1016/j.omta.2026.201826
Cell Death Differ. 2026 Aug 26.

G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.

Sarayu Ramakrishna, Laura Ryan, Sung Min Son, David C Rubinsztein.

The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.

DOI: https://doi.org/10.1038/s41418-026-01853-z
iScience. 2026 Sep 18. 29(9): 117203

Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.

Maria Sakurai, Tomoki Kuwahara, Shoichi Suenaga, Sho Takatori, Taisuke Tomita, Tammy Shalit, Elizabeth Tengstrand, Frank Hsieh, Takeshi Iwatsubo.

  LRRK2, the Parkinson's disease-associated kinase, phosphorylates a subset of Rab GTPases and regulates membrane dynamics. We previously reported that lysosomal stress activates LRRK2 and thereby induces the exocytic secretion of lysosomal contents, but the detailed secretion mechanism remained unclear. Here we found that, under lysosomal stress, endolysosomal luminal and membrane components were secreted with extracellular vesicles (EVs) via LRRK2. Bis(monoacylglycerol)phosphate, an endolysosomal lipid and a urinary marker of LRRK2 activity, was similarly secreted via LRRK2, whereas CD9-positive EVs were not involved. Further dissection of the secreted EVs revealed that Alix-positive EVs were secreted via Rab8a as well as the ESCRT component VPS4, whereas LAMP1/cathepsin B-positive EVs were secreted via Rab10/Rab35, and SNARE proteins syntaxin 2 and VAMP8 regulated the secretion of both EV subtypes. These findings suggest a distinctive stress-induced secretory mechanism whereby LRRK2 facilitates the secretion of multiple EV subtypes by controlling Rab GTPases involved in each pathway.

Keywords:  LRRK2; Parkinson’s disease; extracellular vesicles; lysosomal stress; rab

DOI:  https://doi.org/10.1016/j.isci.2026.117203
Pharmaceutics. 2026 Aug 20. pii: 1038. [Epub ahead of print]18(8):

Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons.

Mohamed Aghyad Al Kabbani, Laura Köhler, Tamara Wied, Daniel Adam, Jennifer Klimek, Hans Zempel.

  Background: Microtubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by posttranslational modifications (PTMs) such as polyglutamylation. In Alzheimer's disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment ('TAU missorting'), dissociates from microtubules, aggregates into neurofibrillary tangles, and contributes to microtubule destabilization and neuronal death. Objectives and Methods: Here, we investigated the role of tubulin tyrosine ligase-like proteins (TTLLs) in TAU missorting and microtubule dysregulation using human-induced pluripotent stem cell (hiPSC)-derived cortical neurons treated with oligomeric amyloid-beta (oAβ) to replicate AD-like conditions. TTLL1, TTLL4, and TTLL6 were selectively knocked down (KD) to assess their impact on TAU missorting and microtubule stability. Fluorescence resonance energy transfer (FRET) microscopy was used to examine proximities between TAU and TTLL proteins. Results: We observed TAU missorting, increased tubulin polyglutamylation, decreased tubulin acetylation associated with microtubule destabilization, and synaptic declustering in oAβ-treated neurons. TTLL1 KD significantly reduced TAU missorting, tubulin polyglutamylation, and synaptic disintegration, while TTLL4 KD showed moderate effects, and TTLL6 KD restored microtubule acetylation. Importantly, TTLL KD did not impair neuritic networks, dendritic complexity, or neuronal activity. FRET microscopy in HEK293T cells revealed a close molecular proximity between TAU and TTLL1 consistent with a potential direct or complex-mediated association, but not with other TTLLs, suggesting a direct role of TTLL1 in TAU-mediated toxicity. Conclusions: Our findings identify TTLL1 as a promising therapeutic target for limiting TAU-associated cytoskeletal pathology in AD. These results support further development of pharmacological or genetic strategies targeting TTLL1 as a disease-modifying approach for AD and related tauopathies.

Keywords:  Alzheimer’s disease; TAU; TTLL; hiPSC neurons; microtubules; neurodegeneration

DOI:  https://doi.org/10.3390/pharmaceutics18081038
Noncoding RNA. 2026 Jul 29. pii: 27. [Epub ahead of print]12(4):

Circular RNAs in Neurons: From Transport to Function.

Nicolò Salvi, Mariangela Morlando.

  Circular RNAs (circRNAs) have recently emerged as a class of abundant and remarkably stable non-coding RNAs preferentially enriched in the nervous system. In neurons, the fine-tuned spatial regulation of gene expression is critical for proper synaptic function; accordingly, several studies have demonstrated that circRNAs exhibit highly compartmentalized localization, specifically within dendrites, axons, and synapses. These spatial localization properties imply the presence of active transport mechanisms, which control the intracellular trafficking of circRNAs. This review highlights the current understanding of circRNA transport in neurons, focusing on the molecular machinery driving synaptic enrichment. We explore the potential role of ribonucleoprotein-based transport as a primary mechanism driving circRNA localization and examine how such spatial distribution influences synaptic plasticity and post-transcriptional gene regulation. Finally, we discuss the clinical implications of these processes, exploring the link between dysregulated RNA transport and the development of neuronal abnormalities.

Keywords:  axons; circular RNA; localization; neuronal disorders; neurons; synapses; transport

DOI:  https://doi.org/10.3390/ncrna12040027
Sci Adv. 2026 Aug 28. 12(35): eaed0049

An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis.

Courtney N Buchanan, Jinyoung Lee, Samaneh Matoo, Jordan A Headen, Marie-Claire Honoree, Molly Conway, Lillian F Thompson, Terika P Smith, Ansley McKay, Cailyn Tosadori, Irene Dalla Costa, Moira Lopez De Leon, Elizabeth Thames, Nora Perrone-Bizzozero, Ashley L Kalinski, Kristy Welshhans, Lauren S Vaughn, Jeffery L Twiss.

Injured axons synthesize the RNA Binding Protein KHSRP that promotes mRNA decay and slows nerve regeneration. Axotomy-induced increase in axoplasmic Ca2+ activates axonal Khsrp translation, and while axonal Ca2+ returns to pre-injury levels within 16 hours post-axotomy, axonal KHSRP remains elevated. Alternating translation of Reg3a and Khsrp sustains KHSRP levels in regenerating axons. Axonal Reg3a mRNA and protein increase proximal to the injury site days after sciatic nerve crush. REG3A stimulates ER Ca2+ release in axons to activate PERK, increase eIF2α phosphorylation, and increase Khsrp translation. Axoplasmic Ca2+ slowly oscillates in growth cones of cultured neurons and Reg3a depletion attenuates growth cone Ca2+ oscillations, decreases KHSRP synthesis and reduces axonal retractive events in cultured neurons, and accelerates peripheral nerve regeneration in vivo. Thus, REG3A regulation of axonal KHSRP synthesis provides a signaling loop that decelerates axon growth through localized mRNA translation.

DOI: https://doi.org/10.1126/sciadv.aed0049