bims-axbals 2026-08-23 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–08–23
thirty-one papers selected by
TJ Krzystek

Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.
Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
Glial control of extracellular α-synuclein propagation in LRRK2 Parkinson's disease.
Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.
A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.
Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.
Generation of GABAergic Neurons from Human Induced Pluripotent Stem Cells Using Doxycycline-Inducible ASCL1/DLX2 Expression at AAVS1.
Regenerative strategies for ALS: stem cells and extracellular vesicles.
SORL1 variant links endosomal amyloid precursor protein mis-sorting to axonal transport defects and neuronal dysfunction.
Human iPSC-Derived Spinal Cord Organoids - The First Electrophysiological Assessment of Neuronal Maturation.
Mitochondrial dynamics in Huntington's disease.
Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.
Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.
A proximity biotinylation approach for the identification of membrane contact site proteins in Toxoplasma gondii.
A ratiometric ER calcium sensor for quantitative comparisons across cell types and subcellular regions.
A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.
Stathmin-2 mediates paracrine hormone regulation of glucagon through lysosomal trafficking in αTC1-6 cells.
Neuromodulatory effects of N-acetyl-L-leucine in a human induced neuronal cell culture system.
Targeting soluble misfolded oligomers in anti-amyloid research.
Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits.
Interactions of LINE-1 ORF1p with proteins and chromatin suggest a role in neuronal physiology.
APTX deficiency is associated with altered neuronal differentiation and alternative splicing in patient-derived neurons.
Analysis of copper toxicity by western blotting of secretory proteins translocated via the Sec61 channel.
iPSC-derived neurospheres: A cellular platform for Tau and Alzheimer's disease immunotherapy.
Histone deacetylases in neurodegeneration and neuronal plasticity.
Allosteric rewiring of mitochondrial stress signaling through Miro1.
Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.
Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.
A Protein Editing Method to Modify Proteins in Live Mammalian Cells.
Current landscape and future perspectives of small-molecule therapeutics for Huntington's disease: From rational design to clinical translation.

iScience. 2026 Aug 21. 29(8): 116866

Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.

Erin M Smith, Natali L Chanaday, Sandra Maday.

  Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by Galectin-3 recruitment to lumenal lysosomal β-galactosides, disrupted lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT (endosomal sorting complex required for transport) repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GTPase-activating protein (GAP), TBC1D15, was more robustly activated in astrocytes. By contrast, the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway, mediating lipid transfer between the endoplasmic reticulum (ER) and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.

Keywords:  ESCRT; LLOMe; ORP9; PI4K2A; TBC1D15; astrocyte; lysosomal damage; neuron

DOI:  https://doi.org/10.1016/j.isci.2026.116866
bioRxiv. 2026 Jul 27. pii: 2026.07.26.740405. [Epub ahead of print]

Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.

Ashton M Spillman, Eric B Alsop, Lauren M Gittings, Krystine Garcia-Mansfield, Ignazio Piras, Anna Bonfitto, Melissa N Martinez, Ritin Sharma, Kim R Preller, Matthew Huentelman, Patrick Pirrotte, Kendall Van Keuren-Jensen, Rita Sattler.

Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.

DOI: https://doi.org/10.64898/2026.07.26.740405
Autophagy. 2026 Aug 16.

Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.

Eva Klinman, Ji-Sun Kwon, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.

  How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in macroautophagy/autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals > 65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by promoting autophagosome generation through TFEB, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Partial organelle recovery occurred after inducing mitophagy or inhibiting mitochondrial fission. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in mitochondria-intrinsic mechanisms to avoid loss of energy production.

Keywords:  Aging; TFEB; autolysosome; dynamics; live-cell; longitudinal; mitochondria; mitophagy; neuronal

DOI:  https://doi.org/10.1080/15548627.2026.2719435
Adv Immunol. 2026 ;pii: S0065-2776(26)00018-0. [Epub ahead of print]171 215-246

Glial control of extracellular α-synuclein propagation in LRRK2 Parkinson's disease.

Indrani Datta, Dibyam Debasish Sahu.

  Parkinson's disease (PD) pathology extends well beyond dopaminergic neuronal loss, with glial cells-microglia and astrocytes-emerging as active architects of α-synuclein spread rather than passive bystanders. This review synthesises current evidence on how mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), the most common genetic cause of familial PD, fundamentally corrupt glial handling of extracellular α-synuclein. We first outline the biology of extracellular α-synuclein-its cellular sources, conformational spectrum, prion-like propagation mechanisms, and principal glial clearance routes-before examining LRRK2 domain architecture, its downstream Rab GTPase signalling cascade, and the cellular processes it governs in glia. We then detail how LRRK2 mutations reconfigure microglial responses: driving constitutive NLRP3 inflammasome priming, impairing phagolysosomal degradation of α-synuclein aggregates, and redirecting phagocytosed cargo into pathogenic exosomal release via the LRRK2-Rab10-LYTL axis. In astrocytes, LRRK2 mutations disrupt annexin A2-mediated phagocytosis, impair chaperone-mediated autophagy and lysosomal acidification, deplete membrane cholesterol through Rab8A/Rab10 hyperphosphorylation, compromise glutamate transporter surface expression, and promote the secretion of phospho-α-synuclein-enriched extracellular vesicles that are neurotoxic to co-cultured dopaminergic neurons. Crucially, dysfunctional microglia and astrocytes do not operate independently-they form a self-amplifying feed-forward circuit in which microglial cytokines (IL-1α, TNF-α, C1q) drive A1 astrocyte conversion, tunnelling nanotube-mediated aggregate exchange propagates rather than resolves α-synuclein burden, and successive waves of neuronal death perpetuate the cycle. We highlight that these mechanisms are mutation-specific: the GTPase-domain variant I1371V, characterised through our group's patient-derived iPSC platform, drives qualitatively distinct membrane and metabolic dysfunction compared with the kinase-domain variant G2019S, underscoring the need for variant-tailored therapeutic strategies. We review human iPSC-based models-including microglia-like cells, midbrain-patterned astrocytes, and 3D midbrain organoids-that have proven indispensable for resolving cell-autonomous from non-cell-autonomous contributions of LRRK2 mutations. Finally, we evaluate emerging therapeutic strategies targeting LRRK2 kinase activity, NLRP3 inflammasome activation, extracellular α-synuclein immunotherapy, and glial lysosomal enhancement, including intranasal mesenchymal stromal cell-derived small extracellular vesicles. We conclude by identifying key unanswered questions regarding the relative dominance of microglial versus astrocytic clearance at different disease stages, the full pathogenic landscape of understudied LRRK2 variants, and the tractability of glial biomarkers as pharmacodynamic endpoints in clinical trials.

Keywords:  Astrocytes; Extracellular vesicles; Glia; IPSC models; LRRK2; Microglia; NLRP3 inflammasome; Neuroinflammation; Parkinson’s disease; α-Synuclein

DOI:  https://doi.org/10.1016/bs.ai.2026.04.005
Mol Ther Adv. 2026 Sep 10. 34(3): 201822

Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.

Andreia Gomes-Duarte, Jamie K Wong, Alessandro Moro, Svetlana Pasteuning-Vuhman, Wouter Pos, Rob Haselberg, Marina Sogorb-González, Sofia Pascoal, Linda Borst, Madhurima Chatterjee, Martin Giera, Sotirios Tsimikas, Saud A Sadiq, Sander van Deventer.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder defined by progressive motor neuron loss and TDP-43 proteinopathy, yet the upstream drivers of this pathology remain unclear. Oxidized phosphatidylcholines (PC-OxPL) have emerged as potent inducers of proteinopathy in the central nervous system (CNS), but their role in ALS has not been systematically explored. We identify a distinct PC-OxPL signature in the cerebrospinal fluid (CSF) of patients with sporadic ALS (sALS) and show that apolipoprotein E (apoE)-containing particles are the primary PC-OxPL carriers in this compartment. In human iPSC-derived motor neurons, PC-OxPL exposure triggered disease-relevant transcriptional alterations and TDP-43 pathology, establishing PC-OxPL as a mediator of ALS-like neurodegeneration in vitro. To counteract this toxicity, we engineered an Adeno-Associated Virus (AAV)-delivered single-chain antibody fragment (scFv), PC-OxPL-VecTab, targeting PC-OxPL neoepitopes. PC-OxPL-VecTab neutralized PC-OxPL-induced neurotoxicity, reduced TDP-43 aggregation, and prevented motor neuron death and behavioral deficits in a sALS CSF transfer mouse model. Intrathecal delivery of PC-OxPL-VecTab in minipigs achieved broad CNS biodistribution and transgene expression, supporting the feasibility of CNS delivery. These findings position PC-OxPL as a mechanistic contributor to ALS pathogenesis and establish PC-OxPL-VecTab as a therapeutic strategy for ALS with potential broader applicability to disorders associated with PC-OxPL accumulation.

Keywords:  TAR DNA-binding protein 43; amyotrophic lateral sclerosis; apolipoprotein E; gene therapy; oxidized phosphatidylcholines

DOI:  https://doi.org/10.1016/j.omta.2026.201822
bioRxiv. 2026 Jul 28. pii: 2026.07.24.740361. [Epub ahead of print]

A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.

Natalie Barretto, Benjamin T Fullerton, Aidan C Daly, Obadele Casel, Olena Kuksenko, Kristy Kang, Joana Petrescu, Maya Xia, Jacqueline Eschbach, Matthew Leung, Shruti Khiste, Brhan Gebremedhin, Colin Smith, Christopher A Jackson, Hemali Phatnani.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper motor neurons in the motor cortex (MTC) and lower motor neurons in the spinal cord, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the site of ALS symptom onset influences the molecular alterations underlying MN and glial dysfunction and whether these alterations are shared between the MTC and lumbar spinal cord (LSC). To address these questions, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS donors clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS donors. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In contrast to the LSC, we observe layer-specific increases in synaptic signaling in the MTC of ALS donors. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.

DOI: https://doi.org/10.64898/2026.07.24.740361
ACS Pharmacol Transl Sci. 2026 Aug 14. 9(8): 2076-2091

Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.

Joyal Xavier, Meenakshi Singh, Sampada Tamhankar, Kristine Griffett, Rajesh Amin.

  TDP-43 proteinopathy is the defining pathological feature in approximately 50% of frontotemporal lobar degeneration (FTLD) cases, yet the precise mechanism or biochemical transition from nuclear proteostasis to cytoplasmic toxicity remains a critical knowledge gap. While its role in repressing nonconserved cryptic exons is well reported, this review highlights and explores the synergy between site-specific proteolysis and post-translational modification (PTM)-induced phase transitions. We propose a mechanism where primary endoproteolytic cleavage by calpain, caspase, and asparaginyl endopeptidase acts as a "protease switch" to generate a C-terminal fragment that disturbs the nuclear import ability of TDP43. These fragments serve as preferred substrates for coordinated hyperphosphorylation and SUMOylation, which drive widespread transcriptome shutdown. We emphasize that synthesizing a small-molecule bridge between these proteins and TDP-43 reduces aberrant protease-mediated fragmentation and delocalization of many proteins. Therefore, in this review, we highlight several therapeutic drug discovery strategies to intercept TDP-43 at the preaggregation stage and restore its function, offering disease-modifying pathways.

Keywords:  TDP-43 aggregation; frontotemporal dementia; neurodegeneration; proteases

DOI:  https://doi.org/10.1021/acsptsci.6c00171
J Vis Exp. 2026 Jul 31.

Generation of GABAergic Neurons from Human Induced Pluripotent Stem Cells Using Doxycycline-Inducible ASCL1/DLX2 Expression at AAVS1.

Théo Rabin, Anthony Flamier.

Human induced pluripotent stem cells (hiPSCs) offer an unprecedented opportunity to model human neurological diseases in vitro. Reliable generation of defined neuronal populations, such as gamma-aminobutyric acid (GABAergic) neurons, is essential for these studies. This protocol details a robust method for differentiating hiPSCs into GABAergic neurons using a doxycycline-inducible system. The approach relies on the stable integration of transgenes encoding the transcription factors ASCL1 and DLX2 into the safe-harbor adeno-associated virus integration site 1 (AAVS1.) locus via CRISPR/Cas9-mediated knock-in. This targeted integration avoids the transgene silencing often observed with random lentiviral integration. The protocol covers the maintenance of hiPSCs, the nucleofection process for transgene integration, puromycin selection to enrich successfully engineered cells, and the step-by-step differentiation procedure. Upon induction with doxycycline, the engineered hiPSCs rapidly exit the cell cycle, acquire neuronal morphology, and express GABAergic lineage markers within 21 days. Key steps include neuro-induction and subsequent maturation using specific growth factors, as well as potential approaches to improve cellular adhesion during maturation. This standardized method yields enriched populations of induced neurons expressing GABAergic lineage markers, providing a valuable tool for neuroscience research and cellular modeling.

DOI: https://doi.org/10.3791/71804
Discov Nano. 2026 Aug 17. pii: 401. [Epub ahead of print]21(1):

Regenerative strategies for ALS: stem cells and extracellular vesicles.

Trisha Raghunathan, Balaji Parthasarathy, Prajnya Prabhu, Preetham Mahesh, Anandh Dhanushkodi.

  Amyotrophic Lateral Sclerosis (ALS) is caused by progressive degeneration of upper and lower motor neurons. The disease is late onset, and to date, no early diagnosis is possible. Patients with ALS have a 5-year survival rate since diagnosis. Though recent studies highlighted the possible mechanisms of motor neuron degeneration in ALS, the treatment options are extremely limited. This underscores the urgent need to develop effective therapeutic strategies that can prolong patient survival and ultimately slow/halt ALS progression. Extracellular vesicles released from the degenerative milieu contribute to ALS propagation and progression by shuttling misfolded proteins, proinflammatory cytokines, and neurotoxins; thus, they could serve as a biomarker for diagnosis and prognosis. The advancement of stem cell-based therapies for neurodegenerative diseases and the evolving understanding of extracellular vesicles as potential biotherapeutics provide a ray of hope for millions of patients suffering from neurological disorders/neurodegenerative diseases like ALS.

Keywords:  Adult stem cells; Amyotrophic lateral sclerosis; Exosomes; Neurodegeneration; Neuroprotection

DOI:  https://doi.org/10.1186/s11671-026-04820-2
Alzheimers Dement. 2026 Aug;22(8): e71782

SORL1 variant links endosomal amyloid precursor protein mis-sorting to axonal transport defects and neuronal dysfunction.

Miriam Lep, Klara Plesingrova, Jiri Sedmik, Sona Cesnarikova, Monica Feole, Ondrej Bernatik, Victorio Martin Pozo Devoto, Hana Hribkova, Katerina Amruz Cerna, Petr Fojtik, Nadezda Vaskovicova, Simona Bartova, Veronika Pospisilova, Tereza Vanova, Olav Michael Andersen, Dasa Bohaciakova, Jan Raska.

   INTRODUCTION: SORL1 encodes the sorting receptor SORLA, a major genetic contributor to Alzheimer's disease (AD). Although SORL1 loss disrupts endosomal trafficking and promotes amyloidogenic amyloid precursor protein (APP) processing, the functional consequences of specific missense variants in human neurons remain unclear.
METHODS: We used isogenic induced pluripotent stem cell (iPSC)-derived NGN2 neurons and 3D cerebral organoids carrying wild-type, SORL1 p.Y1816C knock-in, or SORL1 knockout alleles. We analyzed SORLA maturation and shedding, APP localization, amyloid-β (Aβ) secretion, endosomal morphology, axonal transport of Rab5+ endosomes and APP, and network activity.
RESULTS: The p.Y1816C variant impaired SORLA maturation and shedding and, together with knockout, caused enlarged early endosomes, APP retention, elevated Aβ secretion, amyloid deposition in organoids, axonal swellings, disrupted axonal transport, and neuronal hyperexcitability.
CONCLUSIONS: The SORL1 p.Y1816C variant is pathogenic in human neurons, and we reveal novel roles for SORLA in axonal transport and neuronal excitability. These findings highlight endosomal trafficking disruption as a central mechanism in AD pathogenesis.

Keywords:  Alzheimer's disease; SORL1; axonal transport; endosomal trafficking; iPSCs; neuronal electrophysiology

DOI:  https://doi.org/10.1002/alz.71782
ACS Chem Neurosci. 2026 Aug 19. 17(16): 3048-3057

Human iPSC-Derived Spinal Cord Organoids - The First Electrophysiological Assessment of Neuronal Maturation.

Oleksandr Ievglevskyi, Denis Zosen, Jordi Requena Osete, Joel C Glover, Ragnhild Elisabeth Paulsen, Srdjan Djurovic, Elena Kondratskaya.

  The spinal cord exhibits a complex cytoarchitecture and neuronal circuitry organization that challenges in vitro replication of its functional integrity. Here we employed a previously published protocol to generate spinal cord organoids (SCOs) from human-induced pluripotent stem cells (hiPSCs). We characterized phenotypic changes in functional neuronal properties in SCO neurons at early developmental stages (15-32 days in culture) using a quantitative electrophysiological approach. Using the whole-cell patch-clamp technique to evaluate electrophysiological properties, we found that SCO neurons exhibited progressive maturation, as evidenced by hyperpolarized resting membrane potentials, increased inward current amplitude, refined action potential kinetics, and the early emergence of mature-type firing patterns. In particular, we show that the spike frequency adaptation phenomenon, which prevails in motor neurons, appears at early stages of SCO neuron development. Immunohistochemical assessment confirmed the expression of key transcription factors in motor neurons (ISLET1 and HB9) and immature spinal interneurons (LHX1/5 and PAX2). Collectively, our findings demonstrate that neurons in hiPSC-derived SCOs exhibit physiological differentiation, which is important for using SCOs to investigate human spinal cord development and advance translational research in CNS disorders and cell replacement therapies.

Keywords:  development; electrophysiological recording; human pluripotent stem cells; neuronal maturation; spinal cord organoids; whole-cell patch clamp

DOI:  https://doi.org/10.1021/acschemneuro.5c00823
J Huntingtons Dis. 2026 Aug 17. 18796397261478163

Mitochondrial dynamics in Huntington's disease.

Beatriz Paiva, Ana Cristina Rego.

  Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.

Keywords:  mitochondria; mitophagy; neurotoxicity; pathogenic mechanisms; preclinical models

DOI:  https://doi.org/10.1177/18796397261478163
Mov Disord. 2026 Aug 18.

Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.

Hari Prasad.



Keywords:  GBA1; Parkinson's disease; lysosomal pH; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.1002/mds.70492
Extracell Vesicle. 2026 Jun;pii: 100100. [Epub ahead of print]7

Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.

Paromita Paul Pinky, Zhong-Min Wang, Purva Khare, Jhanvi R Jhaveri, Abigail Sullivan, Vivek Basudkar, Krithika S Rao, Audrey Lawrence, Adithri Pingali, Kandarp M Dave, Donna B Stolz, Ming Sun, Si-Yang Zheng, Sruti S Shiva, Carol Milligan, Osvaldo Delbono, Devika S Manickam.

  Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1G93A transgenic mouse model of ALS.

Keywords:  ALS; EVs; extracellular vesicles; large EVs; mitochondria; motor neurons; small EVs; spinal cord

DOI:  https://doi.org/10.1016/j.vesic.2025.100100
bioRxiv. 2026 Aug 05. pii: 2026.08.05.743015. [Epub ahead of print]

A proximity biotinylation approach for the identification of membrane contact site proteins in Toxoplasma gondii.

Kaelynn V Parker, Diego Huet.

Inter-organellar communication is crucial for cellular function. Inside the cell, organelles interact with each other via membrane contact sites (MCSs). These structures mediate the close apposition of two organellar membranes to allow for the exchange of metabolites, ions and lipids. Most of what is known about MCSs comes only from a handful of well-studied metazoans, particularly yeast and mammals. Apicomplexans are parasites that drive human disease throughout the world. Yet, little is known about the makeup or function of their MCSs, leaving a gap in our understanding of how organelles communicate beyond conventional model eukaryotes. Here, we used a proximity biotinylation approach to map the surface proteome of three organelles in the model apicomplexan Toxoplasma gondii : the apicoplast-a non-photosynthetic plastid found only in apicomplexans-its single mitochondrion and the endoplasmic reticulum. By subtracting a cytosolic spatial reference, our high-stringency proteomic analysis uncovered candidate proteins localized simultaneously to multiple organellar surfaces suggesting their role as MCS components. We then validate our approach by characterizing a candidate involved in the association between the apicoplast and the mitochondrion. Overall, our findings provide a valuable approach to identify MCSs in apicomplexans and set the stage to apply our approach to other organelles in these pathogens.
Highlights: Generation of surface proteomes for the apicoplast, mitochondrion, and ER in Toxoplasma gondii Mapping of the first endoplasmic reticulum and mitochondrial surface proteomes in T. gondii Identified novel membrane contact site candidate proteinsValidated a membrane contact site candidate mediating mitochondrion-apicoplast interactions.

DOI: https://doi.org/10.64898/2026.08.05.743015
J Gen Physiol. 2026 Sep 07. pii: e202413564. [Epub ahead of print]158(5):

A ratiometric ER calcium sensor for quantitative comparisons across cell types and subcellular regions.

Ryan J Farrell, S Thomas Hennigan, Kirsten G Bredvik, Michael B Hoppa, Timothy A Brown, Timothy A Ryan.

The ER is an important regulator of Ca2+ in cells and dysregulation of ER Ca2+ homeostasis can lead to numerous pathologies. Understanding how various pharmacological and genetic perturbations of ER Ca2+ homeostasis impact cellular physiology would be facilitated by quantitative measurements of ER Ca2+ levels that allow for robust comparisons across conditions. To achieve this, we enhanced our original high dynamic range ER Ca2+ indicator, ER-GCaMP6-150, by fusing it to the HaloTag protein, which when bound to Janelia Fluor (JF) dyes creates a ratiometric ER Ca2+ probe. This probe (ER-Halo-GCaMP6-150) displayed minimal changes to the Ca2+-binding properties compared with our original ER Ca2+ probe as shown through in vitro and in cell Ca2+ calibrations. We describe a method to use this ratiometric probe for quantitative comparisons of ER Ca2+ concentrations and leverage this technique to compare ER Ca2+ levels across cell types and subcellular compartments. Using this approach, we show that the resting concentration of ER Ca2+ in primary dissociated neurons does not differ between excitatory and inhibitory subtypes nor between axonal and somatodendritic compartments. However, resting ER Ca2+ levels in neuronal somas are substantially lower than that measured in embryonic fibroblasts. The ER-Halo-GCaMP6-150 provides a robust tool to directly measure ER Ca2+ levels for studies of ER physiology across cell types and compartments.

DOI: https://doi.org/10.1085/jgp.202413564
Alzheimers Dement. 2026 Aug;22(8): e71680

A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.

Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang.

   INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.

Keywords:  AD; ALS; HD; NAD+; PD; PandaOmics; aging; artificial intelligence; machine learning; mitophagy

DOI:  https://doi.org/10.1002/alz.71680
J Physiol. 2026 Aug 20.

Stathmin-2 mediates paracrine hormone regulation of glucagon through lysosomal trafficking in αTC1-6 cells.

Nelson Chang, Samuel Ugulini, Savita Dhanvantari.

  The secretion of glucagon from the pancreatic alpha (α) cell within the islets of Langerhans is physiologically regulated by nutrients (glucose, amino acids, fatty acids), neurotransmitters and paracrine hormones. Insulin and somatostatin form an intra-islet paracrine network to control glucagon secretion through direct inhibitory effects on α cell secretory granule exocytosis. In a potential new cellular pathway for the regulation of glucagon secretion, we have previously identified the neuronal trafficking protein Stathmin-2 (Stmn2) as a negative regulator of glucagon trafficking and secretion by directing glucagon to degradative lysosomes. In this study, we examined whether insulin and somatostatin direct glucagon to lysosomes in a Stmn2-dependent manner as part of their paracrine mechanisms. Using the αTC1-6 glucagon-secreting cell line and confocal microscopy of both fixed and live cells, we show that insulin and somatostatin direct glucagon, glucagon+LAMP1+ vesicles, and LAMP1-RFP to the intracellular region, away from sites of exocytosis. As visualized in live cells, insulin treatment resulted in the rapid retrograde transport of lysosomes from the cell periphery, and this effect was lost under siRNA-mediated silencing of Stmn2. Somatostatin appeared to enhance the intracellular retention of lysosomes, also in a Stmn2-dependent manner. We determined a possible mechanism for Stmn2 in the regulation of lysosome transport in αTC1-6 cells through the Arf-like small GTPase Arl8, indicating that Stmn2 may function in lysosomal positioning along microtubules. We propose that Stmn2-mediated lysosomal transport may be a potential new pathway through which insulin and somatostatin regulate glucagon secretion in the pancreatic α cell. KEY POINTS: Glucagon is produced by the pancreatic islet alpha cell to maintain blood glucose levels, and its secretion is tightly regulated by the islet hormones, insulin and somatostatin. Insulin and somatostatin are known to inhibit glucagon secretory granule exocytosis. In this study, we report a novel pathway through which insulin and somatostatin may inhibit glucagon secretion by directing glucagon to lysosomes through the actions of stathmin-2, a negative regulator of glucagon secretion. We show that insulin directs glucagon and lysosomes away from sites of exocytosis in a stathmin-2-dependent manner, while somatostatin retains lysosomes intracellularly in a stathmin-2-dependent manner. These results demonstrate a new pathway by which insulin and somatostatin regulate glucagon secretion, furthering our understanding of alpha cell physiology.

Keywords:  alpha cells; diabetes; glucagon; insulin; islets; lysosomes; somatostatin

DOI:  https://doi.org/10.1113/JP291537
Front Immunol. 2026 ;17 1866462

Neuromodulatory effects of N-acetyl-L-leucine in a human induced neuronal cell culture system.

Adriana Rehm, Khadija Boulahyoun, Luisa Klossek, Pia Renk, Tom Pietruschka, Ralf Gold, Jeremias Motte, Anke Salmen.

  N-acetyl-L-leucine (NALL), an acetylated derivative of the amino acid leucine, has been shown to reduce neuronal cell death and neuroinflammation in murine models. Its beneficial effects in patients with the lysosomal storage disease Niemann-Pick Type C have led to recent FDA and EMA approval. However, neuroprotective effects of NALL remain to be further elucidated. In this study, we investigate and characterize the neuroprotective effects of NALL. To this end, we used human induced primary neurons (hiPNs), which were generated from induced pluripotent stem cells derived from reprogrammed renal proximal tubule epithelial cells obtained from either healthy controls (HC) or individuals with relapsing-remitting multiple sclerosis (MS). We demonstrated that NALL exhibits neuroprotective properties in MS- and HC-derived hiPNs subjected to acute damage induced by the microtubule-destabilizing agent nocodazole determined by neurite length. This effect can be blocked by inhibition of transporter-specific NALL uptake. HiPNs from MS donors treated with NALL expressed higher levels of glutamate cysteine ligase (GCL), the ratelimiting enzyme in glutathione synthesis. MS-specific cells are more susceptible to stress induced by the protein kinase inhibitor staurosporine, whereas in HC-specific cells only, NALL is able to modulate this stress induction. In summary, we demonstrate differential responses to induced stress in MS- and HC-specific neurons and the capacity of NALL to modulate neurite outgrowth and stress mechanisms in this cell culture system. NALL may represent an interesting additive treatment for MS or other diseases associated with oxidative stress and neurodegeneration if further substantiated.

Keywords:  NALL; cell culture; hiPNs; multiple sclerosis; neuroprotection; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2026.1866462
Nat Rev Chem. 2026 Aug 20.

Targeting soluble misfolded oligomers in anti-amyloid research.

Pernille Vosbein, Hanbin Mao, Chenguang Lou.

Protein misfolding drives a range of non-curable diseases, such as Alzheimer disease, Parkinson disease, type 2 diabetes and Huntington disease, that devastate tens of millions of patients each year. The pathological proteins are misfolded into soluble oligomers, which eventually evolve into insoluble amyloid plaques. Increasing evidence suggests that soluble oligomers are the primary cytotoxic species leading to amyloidoses. However, the transient, heterogeneous and low-abundance nature of soluble oligomers makes it extremely challenging to study these species using conventional methods. This Review surveys emerging chemical tools developed for in vitro detection, separation and analysis of soluble amyloid oligomers. We exemplify how the present arsenal can be extended to construct individual amyloid oligomers as potential drug targets. Finally, we summarize their technical limits and discuss possibilities of adapting these chemical tools to target specific soluble oligomers in the fight against amyloidoses.

DOI: https://doi.org/10.1038/s41570-026-00867-y
Cell Rep. 2026 Aug 20. pii: S2211-1247(26)00963-0. [Epub ahead of print]45(9): 117885

Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits.

Tuo Yi, Haoyuan Guan, Jun Li, Wei Li, Bei Li, Caihong Zhu.

  TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.

Keywords:  ALS; CP: Cell biology; CP: Neuroscience; FTD; ROS; TAF15; neurodegeneration; neurotoxicity; oxidative stress

DOI:  https://doi.org/10.1016/j.celrep.2026.117885
Life Sci Alliance. 2026 Nov;pii: e202503546. [Epub ahead of print]9(11):

Interactions of LINE-1 ORF1p with proteins and chromatin suggest a role in neuronal physiology.

Sandra Sinnassamy, Olivia Massiani Beaudoin, Berangère Lombard, Damarys Loew, Tom Bonnifet, Magali Fradet, Héloïse Monnet, Thomas Caille, Nicolas Servant, Rajiv L Joshi, Julia Fuchs.

Retrotransposons are emerging as novel regulators of embryonic and brain development. We recently demonstrated that the LINE-1-encoded protein ORF1p is abundantly expressed in adult mouse and human neurons, although its function remains unclear. Here, we characterize the ORF1p interactome in differentiated mouse and human neurons using mass spectrometry and identify novel partners implicated in gene regulation and neuron-specific processes. ORF1p localizes not only to neuronal nuclei, where it associates with chromatin under steady-state conditions, but also to neurites, supporting a role in neuronal physiology. To further explore its nuclear functions, we sorted human post-mortem neurons with high or low nuclear ORF1p levels and performed ORF1p knockdown in cultured human neurons, followed by chromatin accessibility assays. Both approaches revealed consistent patterns of differential chromatin accessibility dependent on ORF1p. Loss of ORF1p also led to the down-regulation of long, neuron-specific genes and altered neurite morphology. Together, these findings point to a physiological role of ORF1p in post-mitotic neurons, mediated through converging interactions with proteins and chromatin.

DOI: https://doi.org/10.26508/lsa.202503546
Neurobiol Dis. 2026 Aug 20. pii: S0969-9961(26)00322-0. [Epub ahead of print] 107577

APTX deficiency is associated with altered neuronal differentiation and alternative splicing in patient-derived neurons.

Zirui Chen, Yihua Huang, Xinyue Hu, Zhirong Yuan, Luqin Wang, Kaibiao Xu, Yawei Jiang, Yue Pan, Yangkun Chen, Jing Liu, Yafang Hu.

  Ataxia with oculomotor apraxia type 1 (AOA1), caused by mutations in the DNA repair protein aprataxin (APTX), leads to progressive neurodegeneration. In this study, we established an AOA1 patient-derived induced pluripotent stem cell (iPSC) and a neuronal differentiation model. We demonstrated that AOA1-derived neurons exhibit neurite morphology and maturation defects correlated with the accumulation of DNA single-strand break (SSB) signals. AOA1-derived neurons showed greater DNA-damage and PAR signals together with lower protein-normalized NAD(H) and ATP after genotoxic exposure. These parallel changes are consistent with metabolic stress but do not establish a PARP1-dependent causal pathway. Bulk transcriptomic profiling and alternative splicing (AS) analysis further revealed widespread transcriptomic dysregulation and altered AS events, particularly enriched in neuronal genes essential for neurite development and synaptic function. Collectively, our findings identify neuronal differentiation, DNA-damage, metabolic, and transcriptomic differences in AOA1 patient-derived cultures and motivate composition-controlled and rescue-based studies of APTX function.

Keywords:  AOA1; APTX; Alternative splicing; DNA single-strand break; iPSC

DOI:  https://doi.org/10.1016/j.nbd.2026.107577
Methods Enzymol. 2026 ;pii: S0076-6879(26)00156-4. [Epub ahead of print]733 253-278

Analysis of copper toxicity by western blotting of secretory proteins translocated via the Sec61 channel.

Smriti Anand, Prateeksha Thakur, Vandana Anjana, Santoshi Acharjee, Rajshree Pal, Sugandh Sharma, Raghuvir Singh Tomar.

  As a trace element, copper plays a vital role in regulating cellular homeostasis by serving as a cofactor for various enzymes. Therefore, maintaining an adequate copper concentration inside the cell is crucial. Even moderate dysregulation of homeostasis can lead to cytotoxicity, protein aggregation, resulting in cell death. One of the significant cellular consequences in Saccharomyces cerevisiae is the inhibition of Sec61-mediated protein translocation in the secretory pathway, resulting in the accumulation of the cytosolic form of precursor secretory proteins, such as Gas1 and CPY, in the cytosol. The accumulation of unprocessed precursor proteins in the cytosol provides a method to read out translocon dysfunction. This chapter describes experimental approaches for analysing copper-induced translocation defects in yeast, with a primary focus on Western blot-based detection of precursor and mature secretory protein species. Given the high conservation of copper homeostasis and the secretory pathway across eukaryotes, these methods offer a robust framework for investigating the molecular mechanisms underlying copper toxicity and its impact on protein folding and maturation. This biochemical assay further enables the identification and characterization of chemical or genetic modulators that mitigate copper-induced translocation defects. Compounds that restore Sec61 function or improve ER targeting and maturation reduce the accumulation of precursor forms and promote the recovery of mature protein species. Thus, this approach provides a robust platform for assessing copper toxicity and for screening chemical agents that rescue ER translocation and protein maturation under metal stress conditions.

Keywords:  CPY; Copper homeostasis; ER; Gas1; Protein aggregation; Sec61 protein translocation; Secretory pathway protein; Western blot

DOI:  https://doi.org/10.1016/bs.mie.2026.05.028
Adv Immunol. 2026 ;pii: S0065-2776(25)00038-0. [Epub ahead of print]171 175-203

iPSC-derived neurospheres: A cellular platform for Tau and Alzheimer's disease immunotherapy.

Subashchandrabose Chinnathambi, Anusree Adityan, Madhura Chandrashekar, Gowshika Velmurugan.

  Alzheimer's disease is the most prevalent type of dementia, which is characterized by a progressive loss of memory and cognitive impairment. The internalization of extracellular Tau and Amyloid-β-induced pluripotent stem cells plays a crucial role in understanding the AD pathology. iPSC-derived neuron, microglia, and astrocyte are used as models to study the spreading of pathological proteins and their contribution in the disease progression. iPSC-derived neurons serve as an essential model for studying AD, particularly in relation to Tau aggregation, prion-like propagation, and the toxic effects of oligomeric amyloid beta. Extracellular Tau, along with oligomeric amyloid beta, enters neurons via endocytosis and macropinocytosis, leading to cellular abnormalities, oxidative stress, and dysfunction in neurons. Additionally, iPSC-derived microglia provide insights into neuroinflammatory responses and neurotoxic effects of Tau aggregation and Amyloid-β, highlighting their combined role in Alzheimer's pathology. Extracellular Tau internalization by microglia involves phagocytosis and exhibits activation response to Tau aggregates, releasing cytokines and undergoing calcium homeostasis. iPSC-derived astrocytes demonstrated a reactive state and disruption in calcium homeostasis upon the exposure of the pathological proteins, contributing to neurodegeneration. Further, the mechanisms of Tau and Amyloid-β internalization in iPSC-derived cells provide insights into disease progression and highlights potential therapeutic targets for neurodegenerative disease.

Keywords:  Alzheimer’s disease; Amyloid-β; Extracellular Tau; IPSC- Astrocyte; IPSC- Microglia; IPSC-Neuron

DOI:  https://doi.org/10.1016/bs.ai.2025.11.001
Methods Enzymol. 2026 ;pii: S0076-6879(26)00239-9. [Epub ahead of print]733 321-366

Histone deacetylases in neurodegeneration and neuronal plasticity.

Bhupesh Mehta, Sinjitha Nambiar, Omkar Shirke, Satyarth Pandita, Yogananda S Markandeya.

  This chapter pulls together current research on how HDAC shuttling between the nucleus and cytoplasm affects neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and epilepsy. It takes a close look at why these shifts in HDAC localization matter so much in brain disease and its implications for new treatments. Histone deacetylases (HDACs) are a big deal when it comes to gene regulation in the brain. They play key roles in both neurodegeneration and the brain's ability to adapt, working inside the nucleus and out in the cytoplasm. This chapter unpacks the molecular mechanisms behind HDAC trafficking-how they move around-highlights the different roles of HDAC isoforms, and compares localization-specific effects. It digs into how HDACs impact protein aggregation and synaptopathies. Some findings stand out: HDAC4 and HDAC1 are tightly controlled by phosphorylation signals, which change their cellular localization and influence neuronal mortality. For example, HDAC6 is majorly involved in cellular trafficking and clearing protein aggregates, whereas HDAC4 aggregation in the nucleus is responsible for driving neuronal toxicity. If HDAC1 undergoes nuclear export, it interacts with motor proteins to impact mitochondrial transport. Drugs that block HDAC6 look promising in preclinical models-they help restore neuronal transport systems and clear protein aggregation. Moving HDAC4 out of the nucleus seems to support better synaptic function and motor skills. As a general rule, HDAC accumulation in the nucleus shuts down genes that keep neurons alive, but keeping them in the cytoplasm helps preserve connections between neurons. You'll also find thorough, practical advice on how to study HDACs in brain research-covering everything from enzyme assays and cell experiments to live animal models, plasticity tracking, drug testing, and data analysis. A major innovation featured here is using CRISPR-based tricks to control exactly where HDACs go inside cells: forced targeting using dCas9 fusions, editing natural localization signals, and even using optogenetics for precise on-demand control. In short, the chapter is a hands-on guide for anyone trying to unravel HDAC mechanisms in diseases like Alzheimer's, Parkinson's, Huntington's, or in studies of brain plasticity. Some standout methods include tracking HDAC localization in the cells, measuring how phosphorylation affects their shuttling, and using HDAC2 inhibitors for cognitive boosts. It also covers isoform-specific approaches in Huntington's models, manipulating HDAC location with CRISPR for deeper insights, and combining live-cell imaging with biochemical and chromatin studies for robust validation. This chapter sheds light on the latest advances, with a strong focus on precision, quantitative results, and translating these findings into real-world applications.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; CRISPR; HDAC; Huntington’s disease; Parkinson’s disease

DOI:  https://doi.org/10.1016/bs.mie.2026.06.025
Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073

Allosteric rewiring of mitochondrial stress signaling through Miro1.

Layla Drwesh, Julia C Fitzgerald.

In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.

DOI: https://doi.org/10.1016/j.chembiol.2026.07.011
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00015-2. [Epub ahead of print]189 205-236

Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.

Audrey Valverde, Hélène Blasco, Philippe Corcia, Olivier Herault, Pierre Magistretti, Laurent Herault, Corrado Cali, Luca Bartesaghi, Jonathan Stone, John Mitrofanis.

  All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.

Keywords:  Amyotrophic lateral sclerosis; Near-infrared light; Neurodegenerative disease; Photobiomodulation; Red light

DOI:  https://doi.org/10.1016/bs.irn.2026.01.013
Neurosci Bull. 2026 Aug 21.

Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.

Ji-Chuan Liu, Wen-Jin Liu, Li-Qiang Yu, Jie Li, Yan-Yun Sun, Shao Li, Quan-Hong Ma.

  Alzheimer's disease (AD) is frequently accompanied by cytoplasmic TDP-43 inclusions, although its pathogenic role remains unclear. Using Immuno-LCM-RNAseq in hippocampal excitatory neurons from APP/PS1 mice, we characterized two distinct TDP-43 states: diffuse cytoplasmic mislocalization (Cyto+) and punctate aggregates (Aggre+). Cyto+ neurons exhibited a compensatory "pre-aggregation" signature characterized by enhanced synaptic organization and long-term potentiation pathways, along with altered nucleocytoplasmic transport, phosphorylation/proteolysis regulation, and lipid dysregulation. Aggre+ neurons showed pronounced transcriptional changes associated with neuronal hyperexcitability, including increased calcium signaling and exocytosis, together with protein polymerization and autophosphorylation, mitochondrial dysfunction, and impaired regenerative pathways. Shared features included persistent lipid dysregulation, altered ApoE signaling, and transcriptional repression. Comparison of these states revealed potential upstream therapeutic targets, including ERK1/2, PI3K, small GTPases, and mRNA splicing pathways. These findings provide a transcriptional framework linking early TDP-43 stress responses to pathological aggregation in AD.

Keywords:  Alzheimer’s disease; Neurodegeneration; Neurodegenerative disease; Neuron; Protein aggregation; TARDBP; TDP-43

DOI:  https://doi.org/10.1007/s12264-026-01698-z
Curr Protoc. 2026 Aug;6(8): e70443

A Protein Editing Method to Modify Proteins in Live Mammalian Cells.

Jenna N Beyer, Kaitlyn Toy, George M Burslem.

  Protein editing, as mediated by protein trans-splicing, offers the ability to manipulate, label, and modify proteins in vitro and in live mammalian cells. This ability to observe and control proteins with this high resolution is a burgeoning area of interest within the chemical biology field. In this protocol, we outline the general approach for setting up a cellular protein editing experiment, emphasizing the planning process for a successful protein editing experiment. Additionally, we include methods to install and subsequently label a click chemistry handle p-azido-phenylalanine, a non-canonical amino acid (ncAA) within the intein donor, such that this ncAA and any label can be edited into a protein in live mammalian cells. Overall, we anticipate that this protocol should serve as a generalizable roadmap for planning and carrying out a protein editing experiment. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Expression of intein donor containing pAzF Basic Protocol 2: Purification and labeling of recombinant intein donor Basic Protocol 3: Preparation of mammalian cells for editing experiments Basic Protocol 4: Protein editing via electroporation.

Keywords:  biology; chemical biology; click chemistry; genome editing; noncanonical amino acid; protein Editing

DOI:  https://doi.org/10.1002/cpz1.70443
Eur J Med Chem. 2026 Aug 17. pii: S0223-5234(26)00669-0. [Epub ahead of print]319 119224

Current landscape and future perspectives of small-molecule therapeutics for Huntington's disease: From rational design to clinical translation.

Yitian Jiang, Xinyi Chen, Zhaoxin Xu, Xiao Chen, Qinjie Wang, Junying Ma, Xiyang Wu, Guangyao Deng, Simeng Li, Haopeng Sun, Yao Chen.

  Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene. Given their therapeutic potential, small-molecule strategies have gained significant traction, leading to the design of numerous lead candidates aimed at diverse pathological hallmarks of HD. These developmental efforts target various facets of the disease, including the inhibition and degradation of mutant huntingtin (mHTT) proteins, alleviation of motor dysfunction, and the provision of neuroprotective effects. For instance, gossypol acetate has been identified to induce the autophagic degradation of mHTT. Furthermore, these small molecules modulate critical signaling pathways within HD neurons, such as the store-operated calcium (SOC) channels, dopamine- and cAMP-regulated phosphoprotein 32 (DARPP-32), ataxia-telangiectasia mutated (ATM)/ataxia-telangiectasia and rad3-related (ATR)-p53 pathway, and the kynurenine (KYN) metabolic pathway. While currently explored small-molecule therapies have demonstrated preclinical efficacy, further clinical investigation is imperative to expand the chemical space of viable HD therapeutics. This review critically summarizes the design, synthesis, and structural motifs of small-molecule candidates, clinically used agents, and antioxidant natural products, providing a structural framework to guide the rational design and development of next-generation anti-HD compounds.

Keywords:  Huntington's disease; Mutant huntingtin and small molecules

DOI:  https://doi.org/10.1016/j.ejmech.2026.119224