bims-axbals 2025-11-16 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2025–11–16
37 papers selected by
TJ Krzystek

MARK2 regulates C9orf72 repeat-associated non-AUG translation.
Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.
The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.
Huntington disease: somatic expansion, pathobiology and therapeutics.
Generation of 3D Human iPSC-Derived Multi-Cell Type Neurospheres for Studying Neuron, Astrocyte, and Microglia Crosstalk.
Quick and robust method for the generation of human iPSC-derived choroid plexus organoids.
Metabolic reprogramming in amyotrophic lateral sclerosis ependymal stem cells by FM19G11 nanotherapy.
Development of a targeted BioPROTAC degrader selective for misfolded SOD1.
Examining iPSC derived motor neuron variability and genome stability monitoring as a solution.
Colocalizing Telomeres With PML or γH2AX Foci by IF-FISH in Mouse Brain Neurons.
Advances and challenges in modeling Charcot-Marie-Tooth type 2A using iPSC-derived models.
miR-133b-3p Mitigates D-Galactose-Induced Hippocampal Neuron Aging Through Autophagy Regulation via the MAPK/ERK Signaling Pathway.
IgM Anti-Ganglioside Binding and Complement Activation in an iPSC-Derived Motor Neuron Model for Multifocal Motor Neuropathy.
Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons.
Structural basis of G6P/Pi transport and inhibition in SLC37A4.
Markers of presymptomatic amyotrophic lateral sclerosis: State of the art, practical implications and perspectives.
Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.
Prime editing for the investigation of aberrant splicing defect associated with a pathogenic PRPH2 variant.
An Autopsy Case of ALS Which Clinically Presented Sporadic Adult-Onset Lower Motor Neuron Disease and Genetically Had p. Leu127Ser (L126S) Variant in SOD1 and SMN2 Deletion.
My Amyotrophic Lateral Sclerosis (ALS) Journey from Weakness to Diagnosis: A Journey of Hope.
The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.
Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS.
Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.
CHI3L1: An Emerging Player in Neuroinflammation and Neurodegeneration.
Drug discovery research with the iPSC models of neurodegenerative diseases.
The Dynamic Roles of Repressor Element 1-Silencing Transcription Factor (REST): A Double-Edged Sword in Neural Health and Disease.
Extracellular Vesicles From Multiple Sclerosis White Matter Exhibit Synaptic, Mitochondrial, Complement and Ageing-Related Pathway Dysregulation.
Post-Golgi Trafficking in Plant Cells.
A STIMulating new view of activity-dependent membrane contact architecture.
The bridge-like lipid transfer protein Vps13 are required for NVJ integrity and nucleophagy.
Programmed axon degeneration: mechanism, inhibition and therapeutic potential.
Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity.
The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.
In situ structural mechanism of epothilone-B-induced CNS axon regeneration.
A redox-dependent switch governing sensory axon degeneration and regeneration.
Sphingolipid and methionine metabolism in aging.
Generation of Human 3D Airway Assembloids for Advanced Modeling.

Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2514182122

MARK2 regulates C9orf72 repeat-associated non-AUG translation.

Yu-Ning Lu, Xiangning Li, Lindsey Hayes, Xiao-Feng Zhao, Jiou Wang.

  Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2α kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2α signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.

Keywords:  MARK2; eIF2α; integrated stress response

DOI:  https://doi.org/10.1073/pnas.2514182122
Acta Neuropathol. 2025 Nov 12. 150(1): 52

Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.

Nikhil B Ghayal, Richard J Crook, Angita Jain, Gunveen Sachdeva, Peizhou Jiang, Shanu F Roemer, Hiroaki Sekiya, Michael A DeTure, Matthew C Baker, Wouter De Coster, Björn Oskarsson, Keith A Josephs, Rosa Rademakers, Marka M van Blitterswijk, Dennis W Dickson.

  Aggregation of TAR-DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases diagnosed with a primary TDP-43 proteinopathy, including FTLD-TDP, FTLD-MND, and MND-TDP. Cases with FTLD-MND and MND-TDP were classified further into PLS, ALS, and PMA based on the relative loss of upper and lower motor neurons. ANXA11 proteinopathy was present in over 40% of FTLD-MND cases. Further, ANXA11 colocalized with TDP-43 in the pathologic inclusions of all FTLD-TDP type C cases, as well as 38 out of 40 FTLD-PLS cases (95%), of which 84% had TDP type B or an unclassifiable TDP-43 proteinopathy and 16% had TDP type C. Genetic analysis excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated two novel ANXA11 proteinopathies strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship between TDP-43 and ANXA11 in neurodegenerative disease, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises a distinct group of molecular pathologies and define three TAP types based on key clinical and neuropathologic characteristics.

Keywords:  Annexin A11; Frontotemporal lobar degeneration; Motor neuron disease; Primary lateral sclerosis; TDP-43

DOI:  https://doi.org/10.1007/s00401-025-02958-4
Acta Neuropathol. 2025 Nov 11. 150(1): 51

The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.

George Tsafaras, Diego Cabezudo, Lot Wetzels, Iraklis Tsakogias, Ajantha Abey, Eduard Bentea, Maria Sanchiz-Calvo, Chris Van den Haute, Richard Wade-Martins, Veerle Baekelandt.

  Aggregated α-synuclein (αSyn) is a pathological hallmark of Parkinson's disease (PD), yet other protein aggregates, including tau, are commonly observed in PD brains. This suggests that PD is not solely a synucleinopathy but may involve multiple, coexisting proteinopathies. Mutations in LRRK2, particularly the G2019S (GS), are the most common cause of familial PD. LRRK2-PD has been associated with both αSyn and tau pathology; however the mechanistic links between LRRK2 dysfunction and protein aggregation remain incompletely defined. Here we opted to investigate whether LRRK2 contributes to αSyn and tau pathology through common molecular pathways or via distinct cellular mechanisms. Viral vector-mediated αSyn overexpression in GS LRRK2 knock-in mice led to enhanced dopaminergic neurodegeneration, increased phosphorylated αSyn levels, pronounced neuroinflammation, and accumulation of lysosomal proteins, suggesting impaired αSyn clearance and immune activation as key drivers. Human iPSC-derived dopaminergic neurons from GS LRRK2 PD patients mirrored these findings. In contrast viral vector-mediated overexpression of tau in GS LRRK2 knock-in mice promoted tau phosphorylation but did not significantly affect neuroinflammation, lysosomal markers, or neurodegeneration, indicating a primarily cell-autonomous mechanism. Our results reveal a mechanistic divergence in how GS LRRK2 impacts αSyn and tau pathologies, supporting the notion that LRRK2 kinase activity contributes to PD pathogenesis through different pathways, thereby highlighting its potential as a therapeutic target in both familial and sporadic PD.

Keywords:  Alpha-synuclein; LRRK2; Parkinson’s disease; Tau

DOI:  https://doi.org/10.1007/s00401-025-02956-6
Nat Rev Neurol. 2025 Nov 13.

Huntington disease: somatic expansion, pathobiology and therapeutics.

Jasmine Donaldson, Davina Hensman Moss, Marc Ciosi, Karen Usdin, Gabriel Balmus, Darren G Monckton, Sarah J Tabrizi.

Expansion of simple DNA repeats causes over 45 human, predominantly neurodegenerative, inherited disorders. Huntington disease is a fatal, inherited, neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene (HTT), resulting in a toxic polyglutamine tract in the huntingtin protein. The disease leads to progressive motor, cognitive and psychiatric decline, primarily resulting from loss of medium spiny neurons in the striatum. Although Huntington disease has long been viewed as a consequence of age-dependent toxicity from mutant huntingtin, genome-wide association studies have identified genetic modifiers, mostly DNA repair genes, that significantly influence disease onset and progression. These findings point to somatic CAG repeat expansions in affected tissues as a key pathological mechanism. This emerging paradigm suggests that disease progression is not solely protein-driven but also shaped at the DNA level, a mechanism that is shared among other repeat expansion disorders. Therapeutically, this discovery opens new opportunities: interventions to limit somatic repeat expansion might be effective across multiple repeat expansion diseases and, when combined with disease-specific approaches, such as huntingtin lowering in Huntington disease, might offer more effective and longer-lasting clinical benefits than either strategy in isolation. This approach also poses challenges, determining the optimal point for therapeutic intervention and how best to establish phenotypic improvement in clinical trials when the target tissue is the brain.

DOI: https://doi.org/10.1038/s41582-025-01159-7
Bio Protoc. 2025 Nov 05. 15(21): e5493

Generation of 3D Human iPSC-Derived Multi-Cell Type Neurospheres for Studying Neuron, Astrocyte, and Microglia Crosstalk.

Stefan Wendt, Christopher Lee, Wenji Cai, Ada J Lin, Jessica Huang, V Poon, Xianyuan Xiang, Wei Hong, Brian A MacVicar, Haakon B Nygaard.

  Three-dimensional (3D) human brain tissue models derived from induced pluripotent stem cells (iPSCs) have transformed the study of neural development and disease in vitro. While cerebral organoids offer high structural complexity, their large size often leads to necrotic core formation, limiting reproducibility and challenging the integration of microglia. Here, we present a detailed, reproducible protocol for generating multi-cell type 3D neurospheres that incorporate neurons, astrocytes, and optionally microglia, all derived from the same iPSCs. While neurons and astrocytes differentiate spontaneously from neural precursor cells, generated by dual SMAD-inhibition (blocking BMP and TGF-b signaling), microglia are generated in parallel and can infiltrate the mature neurosphere tissue after plating neurospheres into 48-well plates. The system supports a range of downstream applications, including functional confocal live imaging of GCaMP6f after adeno-associated virus (AAV) transduction of neurospheres or immunofluorescence staining after fixation. Our approach has been successfully implemented across multiple laboratories, demonstrating its robustness and translational potential for studying neuron-glia interactions and modeling neurodegenerative processes. Key features • Reproducible human iPSC-derived 3D neurosphere multi-cell type tissue culture system. • Optional addition of microglia allows for studying neuron-microglia interaction in vitro in 3D. • Reliable spontaneous activity offers functional tissue culture readouts of neural firing. • System allows modeling of human brain diseases, such as Alzheimer's disease.

Keywords:  3D neural tissue; In vitro disease modeling; Microglia; Neuro–glia interaction; iPSC-derived cells

DOI:  https://doi.org/10.21769/BioProtoc.5493
Hum Cell. 2025 Nov 11. 39(1): 5

Quick and robust method for the generation of human iPSC-derived choroid plexus organoids.

Rodi Kado Abdalkader, Takuya Fujita.

  The choroid plexus (ChP) is a key brain structure responsible for cerebrospinal fluid (CSF) production and forms a selective barrier that regulates brain homeostasis and immune surveillance. In vitro models of ChP are essential for studying CSF dynamics, viral entry, neuroinflammation, and CNS drug transport; yet current organoid protocols remain complex, slow, and difficult to reproduce. Here, we report a quick and robust method for the generation of human iPSC-derived ChP organoids that is xeno-free and serum-free, scalable, and reproducible. Early GSK3β inhibition and transient WNT modulation guide organoids toward cystic ChP-enriched structures, confirmed by ventricle-like morphology, and expression of canonical markers (TTR, ZO-1). This minimal workflow enables rapid production of ChP-like organoids that recapitulate ChP morphology and marker expression, providing a potential platform for studies of cerebrospinal fluid physiology, barrier modelling, and translational neuroscience.

Keywords:  IPSCs; cerebrospinal fluid; choroid plexus; organoids

DOI:  https://doi.org/10.1007/s13577-025-01320-w
Sci Rep. 2025 Nov 13. 15(1): 39847

Metabolic reprogramming in amyotrophic lateral sclerosis ependymal stem cells by FM19G11 nanotherapy.

Marco Cattaneo, Marcella Bonanomi, Cristina Chirizzi, Claudia Malacarne, Eleonora Giagnorio, Giorgia Farinazzo, Silvia Bonanno, Danilo Porro, Giuseppe Lauria, Pierangelo Metrangolo, Francesca Baldelli Bombelli, Daniela Gaglio, Stefania Marcuzzo.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the motor cortex, brainstem, and the spinal cord. In response to neurodegeneration, spinal cord exhibits ineffective regenerative attempt, thus suggesting that therapeutic strategies aimed at enhancing regenerative capacity of ependymal stem/progenitor cells (epSPCs), residing in the spinal cord, could promote neurogenesis. Dysregulated levels of metabolites might disturb epSPC differentiation, and their restoration might favour neurogenesis. This study aimed to investigate the metabolomic profile of epSPCs from ALS mice to identify altered metabolites as novel therapeutic targets for precision treatment. We performed a metabolome analysis to investigate changes in epSPCs from ALS compared to control male mice (B6SJL-Tg (SOD1*G93A)1Gur/J) and treated the epSPCs with FM19G11-loaded nanoparticles (NPs) to reestablish metabolic balance. Metabolomics analysis revealed significant changes in ALS epSPCs compared to controls. In vitro treatment with FM19G11-loaded nanoparticles (NPs) restored key metabolic networks, particularly in pathways related to glucose, glutamate and glutathione metabolism. These findings highlight the potential of FM19G11-loaded NPs to revert metabolic dysregulation in ALS epSPCs, providing a basis for innovative metabolic therapies and precision medicine approaches to counteract motor neuron degeneration in ALS and other motor neuron diseases.

Keywords:  Amyotrophic lateral sclerosis; Ependymal stem progenitor cells; G93A-SOD1 mouse model; Metabolomics; Nanomedicine.

DOI:  https://doi.org/10.1038/s41598-025-23553-3
Nat Commun. 2025 Nov 10. 16(1): 9713

Development of a targeted BioPROTAC degrader selective for misfolded SOD1.

Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke McAlary, Jeremy S Lum, Justin J Yerbury.

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1G93A mouse model of ALS. Delayed disease progression is associated with protection of motor neurons, a reduction of insoluble SOD1 accumulation and preservation of innervated neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-025-65481-w
Sci Rep. 2025 Nov 12. 15(1): 39670

Examining iPSC derived motor neuron variability and genome stability monitoring as a solution.

Finbar Gaffey, David McCoull, Egle Vaitone, Erin Hedges, Christopher Lovejoy, Zhi Yao, Paul D Wright, Richard J Mead, Will Stebbeds.

Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) offer a promising model system for understanding motor neuron diseases (MNDs) and advancing drug discovery. However, variability in differentiation outcomes presents a major barrier to reproducibility and model reliability. This study evaluates a widely adopted small molecule protocol for MN differentiation to quantify variability and identify its sources within an industrial setting. Analysing data from 15 differentiation sets across 8 cell lines, we found that non-genetic factors - particularly induction set and operator - were the predominant sources of variability, outweighing the contribution from cell line genetics. We further demonstrated that iPSC genomic instability, as assessed by a targeted RT-qPCR assay for common karyotypic abnormalities, significantly affected differentiation efficiency and purity. Cultures derived from genomically stable iPSCs exhibited reduced variance and improved MN marker expression profiles. These findings support routine genomic assessment of iPSCs as a practical and effective strategy to enhance the reliability of iPSC-derived MN models, thereby improving their utility in preclinical MND research and therapeutic development.

DOI: https://doi.org/10.1038/s41598-025-23378-0
Bio Protoc. 2025 Nov 05. 15(21): e5485

Colocalizing Telomeres With PML or γH2AX Foci by IF-FISH in Mouse Brain Neurons.

Anna Konopka.

  Telomere length maintenance is strongly linked to cellular aging, as telomeres progressively shorten with each cell division. This phenomenon is well-documented in mitotic, or dividing, cells. However, neurons are post-mitotic and do not undergo mitosis, meaning they lack the classical mechanisms through which telomere shortening occurs. Despite this, neurons retain telomeres that protect chromosomal ends. The role of telomeres in neurons has gained interest, particularly in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where aging is a major risk factor. This has sparked interest in investigating telomere maintenance mechanisms in post-mitotic neurons. Nevertheless, most existing telomere analysis techniques were developed for and optimized using mitotic cells, posing challenges for studying telomeres in non-dividing neuronal cells. Thus, this protocol adapts an already established technique, the combined immunofluorescence and telomere fluorescent in situ hybridization (IF-FISH) on mitotic cells to study the processes occurring at telomeres in cortical neurons of the mouse ALS transgenic model, TDP-43 rNLS. Specifically, it determines the occurrence of DNA damage and the alternative lengthening of telomeres (ALT) mechanism through simultaneous labeling of the DNA damage marker, γH2AX, or the ALT marker, promyelocytic leukemia (PML) protein, together with telomeres. Therefore, the protocol enables the visualization of DNA damage (γH2AX) or the ALT marker (PML) concurrently with telomeres. This technique can be successfully applied to brain tissue and enables the investigation of telomeres specifically in cortical neurons, rather than in bulk tissue, offering a significant advantage over Southern blot or qPCR-based techniques. Key features • This protocol enables the labeling of telomeres in mouse brain tissue prepared from paraffin-embedded brain sections. • This method facilitates concurrent labeling of proteins that are colocalized at telomere sites.

Keywords:  ALS; DNA damage; IF-FISH; Mouse neurons; Neurodegeneration; PML; Telomere; Telomere maintenance

DOI:  https://doi.org/10.21769/BioProtoc.5485
Stem Cell Reports. 2025 Nov 13. pii: S2213-6711(25)00315-7. [Epub ahead of print] 102711

Advances and challenges in modeling Charcot-Marie-Tooth type 2A using iPSC-derived models.

Mafalda Rizzuti, Elisa Pagliari, Martina D'Agostino, Linda Ottoboni, Valeria Parente, Giacomo Pietro Comi, Stefania Corti, Federica Rizzo, Elena Abati.

  Charcot-Marie-Tooth type 2A (CMT2A) is an inherited sensory-motor axonopathy caused by mutations in the Mitofusin2 (MFN2) gene, coding for MFN2 protein. No curative treatment has been developed to date. The advent of induced pluripotent stem cell (iPSC) has provided unprecedented opportunities to understand complex neurological disorders. In CMT2A research, patient-specific iPSCs can be differentiated in motor and sensory neurons, thereby establishing reliable in vitro disease models. Here, we review current available iPSC-based models of CMT2A, focusing on pathogenetic insights derived from these studies and discussing challenges and potential of iPSC-derived models in elucidating disease mechanisms, providing innovative platforms for testing, and developing novel effective therapeutic strategies.

Keywords:  CMT2A; MFN2; iPSCs; motor neurons; sensory neurons

DOI:  https://doi.org/10.1016/j.stemcr.2025.102711
Mol Neurobiol. 2025 Nov 11. 63(1): 28

miR-133b-3p Mitigates D-Galactose-Induced Hippocampal Neuron Aging Through Autophagy Regulation via the MAPK/ERK Signaling Pathway.

Yang Cao, Chen Zhao, Jiaxin Li, Qiang Gao, Chunmei Lv, Jiao Wang, Na Qiang, Wenwen Zhang, Huiyu Su, Xinyu Min, Jinfeng Liu, Xiaoqi Dai, Hui Zhu.

  Although remarkable progress has been achieved in contemporary medical research, effective drugs or prophylactic approaches targeting neurodegenerative diseases associated with aging are still limited. Increasing evidence suggests that microRNAs (miRNAs) are closely associated with age-related neurological diseases, positioning them as novel therapeutic targets. Autophagy in neurons participates in the renewal of damaged or aged endoplasmic reticulum, mitochondria, other organelles, and aggregated proteins during aging. This study evaluated the anti-aging mechanism of miR-133b-3p in D-galactose (D-gal)-induced hippocampal neurons. A mouse aging model was established by long-term D-gal injection and compared with 18-month-old naturally aged mice to verify and confirm the successful establishment of the aging model, providing a more reliable experimental basis for exploring the changes in mechanisms during aging.Compared with young mice, the D-gal group and the 18 M group showed decreased learning and memory abilities, altered neuronal structures, downregulated miR-133b-3p expression, and inhibited MAPK/ERK signaling pathway and autophagy. In addition, in the D-gal-induced HT22 cell senescence model, autophagy was inhibited, and the expression of the age-related protein p53 was downregulated. We also found that miR-133b-3p overexpression under aging conditions can activate autophagy via the MAPK/ERK signaling pathway and exert neuroprotection in hippocampal neurons. However, the effect of miR-133b-3p in reducing cellular aging damage was weakened when the MAPK/ERK signaling pathway was blocked or autophagy was inhibited.This study revealed the significant mechanism whereby miR-133b-3p protects hippocampal neurons in aging mice. miR-133b-3p alleviates D-gal-induced cellular aging damage by activating autophagy through the MAPK/ERK signaling pathway.

Keywords:  Aging; Autophagy; Hippocampal neuron; MAPK/ERK; miR-133b-3p

DOI:  https://doi.org/10.1007/s12035-025-05323-4
Neurol Neuroimmunol Neuroinflamm. 2026 Jan;13(1): e200482

IgM Anti-Ganglioside Binding and Complement Activation in an iPSC-Derived Motor Neuron Model for Multifocal Motor Neuropathy.

Daniëlle Krijgsman, Kim Dijkxhoorn, Elisabeth de Zeeuw, Lauri M Bloemenkamp, Jeroen W Bos, Ruben P A van Eijk, Inge Van de Walle, Ruth Huizinga, Bart C Jacobs, Jeanette H W Leusen, R Jeroen Pasterkamp, C Erik Hack, Kevin Budding, W Ludo van der Pol.

BACKGROUND AND OBJECTIVES: Multifocal motor neuropathy (MMN) is an asymmetric motor neuropathy driven by IgM autoantibodies targeting gangliosides, particularly GM1. In this study, we investigated the relationship between IgM seropositivity, complement activation, and clinical parameters using an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model of MMN.
METHODS: We used serum samples from 137 patients with MMN to assess IgM binding and subsequent C3 fixation to iPSC MNs and their correlation with clinical parameters, including muscle strength expressed as MRC sum scores, obtained from patient records. In addition, we tested the efficacy of IV immunoglobulin (IVIg) and specific complement inhibitors to prevent C3 fixation to MNs.
RESULTS: We observed increased IgM binding to iPSC MNs using serum samples from patients with MMN compared with those from healthy controls, which correlated with IgM anti-ganglioside antibody titers. Higher antibody binding correlated with levels of C3 fixation, more severe weakness, and the need for higher IVIg doses. Complement activation, but not IgM binding, also correlated with vibration sense abnormalities, brachial plexus MRI abnormalities, and the degree of axonal damage. At therapeutic concentrations, IVIg moderately inhibited complement activation (34%-54%) while specific complement inhibitors were highly effective (89.1%-98.7%) in the iPSC MN model.
DISCUSSION: This study demonstrates that IgM antibodies in serum samples from patients with MMN induce complement activation on iPSC MNs, which correlates significantly with clinical outcomes. In addition, our findings indicate that complement inhibitors offer a potentially targeted novel therapeutic strategy for MMN and that our iPSC MN model is a viable preclinical screening platform.

DOI: https://doi.org/10.1212/NXI.0000000000200482
Mol Neurobiol. 2025 Nov 13. 63(1): 37

Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons.

Šárka Danačíková, Petr Pecina, Alena Pecinová, Jan Svoboda, David Vondrášek, Davide Alessandro Basello, Tomáš Čajka, Daniel Hadraba, Tomáš Mráček, Vladimír Kořínek, Jakub Otáhal.

  Neuronal differentiation requires extensive metabolic remodeling to support increased energetic and biosynthetic demands. Here, we present an integrated multi-omics and functional characterization of metabolic transitions during early differentiation of human induced pluripotent stem cells (iPSCs) into excitatory cortical neurons using doxycycline-inducible overexpression of neurogenin-2 (NGN2). We analyzed parental iPSCs and induced neurons (iNs) at days 7 and 14 of differentiation, integrating gene expression profiling, label-free quantitative proteomics, high-resolution respirometry, fluorescence lifetime imaging microscopy (FLIM), and 13C₆-glucose metabolic flux analysis. Our data reveal progressive metabolic remodeling associated with neuronal maturation, including enhanced oxidative phosphorylation, increased mitochondrial content, and respiratory capacity. Proteomic analyses showed upregulation of mitochondrial and antioxidant pathways, while FLIM indicated a progressive increase in enzyme-bound NAD(P)H, consistent with a shift toward oxidative metabolism. Notably, 13C₆-glucose tracing revealed delayed labeling of the intracellular pool of fully labeled glucose and tricarboxylic acid cycle metabolites, together with enhanced labeling of pentose phosphate pathway intermediates and glutathione in iNs, indicating a shift toward biosynthetic and antioxidant glucose utilization during differentiation. Despite this enhancement in mitochondrial function, differentiated neurons maintained glycolytic activity, suggesting metabolic flexibility. Our results define the first week of differentiation as a critical window of metabolic specialization and establish NGN2-iPSC-derived cortical neurons as a versatile and well-characterized model system for investigating bioenergetic remodeling during early human neurodevelopment. It provides a robust foundation for mechanistic insights and high-throughput evaluation of metabolic pathways relevant to human disease.

Keywords:  Cellular bioenergetics; Human iPSCs; Metabolic flux analysis; Neuronal differentiation; Proteomics; Respirometry

DOI:  https://doi.org/10.1007/s12035-025-05284-8
Nat Struct Mol Biol. 2025 Nov 12.

Structural basis of G6P/Pi transport and inhibition in SLC37A4.

Dong Zhou, Yang Zhang, Nanhao Chen, Shitang Huang, Chen Song, Zhe Zhang.

Glycogen storage disease type Ib (GSD-Ib), caused by loss-of-function mutations in the endoplasmic reticulum transporter SLC37A4, disrupts glucose homeostasis through impaired glucose-6-phosphate (G6P)/phosphate (Pi) antiport. Despite its central role in glycogen metabolism and immune regulation, the structural mechanisms governing SLC37A4's transport cycle and pathological dysfunction remain elusive. Here we report cryo-electron microscopy structures of human SLC37A4 in four functional states, capturing conformational transitions between lumen-facing and cytoplasm-facing states. Combined with mutational analysis, molecular dynamics simulations and functional assays, we identify a conserved substrate-binding pocket that alternately accommodates G6P and Pi through electrostatic complementarity and domain-dependent interactions. We further demonstrate that the high-affinity inhibitor S-4048 sterically occludes the cytoplasmic entry pathway by trapping the transporter in a cytoplasm-facing conformation. Our work elucidates the molecular pathology of GSD-Ib-linked mutations and provides a structural framework for developing therapies targeting this transporter in metabolic diseases.

DOI: https://doi.org/10.1038/s41594-025-01711-5
Rev Neurol (Paris). 2025 Nov;pii: S0035-3787(25)00581-8. [Epub ahead of print]181(9): 893-908

Markers of presymptomatic amyotrophic lateral sclerosis: State of the art, practical implications and perspectives.

M-H Soriani, H Blasco, P Corcia, V Danel-Brunaud, A Desmaison, P-F Pradat, G Querin, P Vourch, N Guy.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an identified genetic origin in 10-15% of cases, mainly involving C9orf72 and SOD1 mutations. The increasing number of genetically confirmed ALS cases has led to a growing identification of asymptomatic mutation carriers. While riluzole remains the standard treatment, mutation-specific therapies such as tofersen, that was recently approved in SOD1-ALS, are emerging. In this context, the identification of presymptomatic biomarkers is crucial for monitoring genetically at-risk individuals. Plasma neurofilament light chain can increase up to 3.5years before symptom onset in C9orf72 carriers. Metabolic and neuroimaging alterations together with cognitive or behavioral changes, that are sometimes detectable decades prior to diagnosis, have also been observed. These biomarkers may support early surveillance and intervention strategies. The present review provides an overview of current evidence on presymptomatic biomarkers in ALS mutation carriers and their potential role in genetic counseling, monitoring, and early therapeutic decisions.

Keywords:  Amyotrophic lateral sclerosis; C9orf72 mutation; Frontotemporal dementia; Presympomatic biomarkers; SOD1 mutation

DOI:  https://doi.org/10.1016/j.neurol.2025.07.008
Autophagy. 2025 Nov 10.

Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.

Juncai Ma, Chaorui Li, Xiaohong Zhuang.

  Mitochondrial dynamics play critical roles in mitochondrial quality control to maintain mitochondrial function. In plants, mitochondria are typically discrete rather than networked, but how damaged mitochondrial contents can be efficiently removed remains unclear. In a recent study, we demonstrate that the plant-specific fission regulator ELM1, together with DRP3 and the autophagic adaptor SH3P2, orchestrates mitochondrial dynamics and mitophagosome assembly for piecemeal mitophagy under heat stress condition. Deficiency in mitochondrial fission activity delays mitophagosome formation and leads to an accumulation of megamitochondria that are partially sequestered by phagophore intermediates positive for ATG8 and NBR1. Further 3D electron tomography analysis reveals that phagophore fragments expand toward the constriction sites of the abnormal protrusions from the mitochondrial body. These findings highlight an unappreciated role of plant mitochondrial fission machinery in coupling with autophagy machinery for mitochondrial segregation and mitophagosome assembly, establishing a mechanistic framework for plant mitophagy in stress resilience.

Keywords:  ELM1; SH3P2; mitochondrial dynamics; mitochondrial fission; piecemeal mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2587051
Mol Ther Nucleic Acids. 2025 Dec 09. 36(4): 102740

Prime editing for the investigation of aberrant splicing defect associated with a pathogenic PRPH2 variant.

Bruna Lopes da Costa, Kyle M Helms, Keith Theodore, Yi-Ting Tsai, Salvatore Marco Caruso, Siyuan Liu, Jose Ronaldo Lima de Carvalho, Nicholas D Nolan, Saleha Tahir, Christopher D Makinson, Stephen H Tsang, Peter M J Quinn.

  The human Peripherin 2 (PRPH2) gene, essential for the structure and function of photoreceptor outer segments, is implicated in a range of inherited retinal diseases (IRDs). This study focuses on the pathogenic c.828+1G>A PRPH2 splice site variant. We employed prime editing (PE) technology to install and correct this variant in human induced pluripotent stem cells (hiPSCs). We developed an all-in-one PE construct, featuring a GFP reporter to facilitate the identification of successfully edited clones. The resulting heterozygous and homozygous hiPSC clones exhibited no detectable off-target mutations or karyotype abnormalities. Crucially, we found in hiPSCs and DD50/DD100 precursor hiPSC-derived retinal organoids that the c.828+1G>A PRPH2 mutation leads to activation of a cryptic splice site and intron retention, forming a mutant transcript. Importantly, correction of the c.828+1G>A PRPH2 mutation in the homozygous hiPSC clone resulted in the restoration of the canonical PRPH2 transcript and a reduction of the mutant transcript. Our findings highlight the potential of PE as a precise and safe method for installing and correcting pathogenic PRPH2 mutations in hiPSCs, paving the way for future genotype-phenotype studies and therapy development for PRPH2-mediated IRDs.

Keywords:  MT: RNA/DNA Editing; PRPH2 c.828+1G>A splice site variant; PRPH2-mediated IRDs; hiPSC; prime editing; retinal organoids; retinitis pigmentosa

DOI:  https://doi.org/10.1016/j.omtn.2025.102740
Neuropathology. 2025 Dec;45(6): e70032

An Autopsy Case of ALS Which Clinically Presented Sporadic Adult-Onset Lower Motor Neuron Disease and Genetically Had p. Leu127Ser (L126S) Variant in SOD1 and SMN2 Deletion.

Kimiko Inoue, Harutoshi Fujimura, Kayo Ueda, Hisahide Nishio, Hiroya Naruse, Yuishin Izumi.

  Herein, we report an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) with a p. L127S (L126S) SOD1 variant, SMN2 deletion and one hybrid SMN. A 43-year-old Japanese man noticed muscle weakness in his left lower extremity. At the age of 51, his muscle strength was moderately diminished in the upper extremities and severely in the lower extremities with hyporeflexia. At the age of 55, he started noninvasive intermittent ventilation (NIV) during nighttime. At the age of 57, he developed dysphagia and died of pneumonia. The total clinical course was 14 years and 8 months (13 years 9 months until NIV). Pathologically we found severe loss of lower motor neurons, moderate neuronal loss in Clarke's nuclei and mild grumose degeneration of the dentate nucleus. The primary motor cortex was well preserved and the pyramidal tracts showed vague myelin pallor in the lumbar cord. There were a few conglomerate hyaline inclusions (CHIs) that were negative for Bodian staining. Immunohistochemically, CHIs were positive for phosphorylated neurofilament (pNF) and were stained with Uq and SOD1 to varying degrees. Some CHIs contained granular-like components positive for p62. A post-mortem genetic test revealed that the patient had 2 copies of SMN1, 0 copies of SMN2, and one hybrid gene with exon 1 to 7 of SMN2 and SMN1 exon 8. Additional gene research elucidated a heterozygous SOD1 p. Leu127Ser (L126S) mutation. Compared to previous reports of ALS with the same mutation, the distribution of degenerative lesions was similar. It has been suggested that SMN2 deletion may not be directly implicated in lower motor neuron pathology, but further research is needed to confirm this. Further accumulation of cases is necessary to determine the effect of SMN2 on SOD1-ALS.

Keywords:   SMN2 ; SOD1 ; amyotrophic lateral sclerosis; hybrid SMN; p. L127S

DOI:  https://doi.org/10.1111/neup.70032
Healthcare (Basel). 2025 Oct 30. pii: 2754. [Epub ahead of print]13(21):

My Amyotrophic Lateral Sclerosis (ALS) Journey from Weakness to Diagnosis: A Journey of Hope.

Sherry Wityshyn, Nitesh Sanghai, Geoffrey K Tranmer.

  Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a progressive neurodegenerative disease that attacks and kills motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy, eventually causing respiratory failure and death within 2-5 years after diagnosis. By 2040, the global population of individuals living with ALS is projected to approach 400,000. Since ALS was discovered by Charcot 150 years ago, only two drugs (Edaravone and Riluzole) have been available, offering modest clinical benefits in slowing disease progression. The increasing number of cases, along with the high costs of treatment and care, creates a growing burden on communities and the healthcare system. However, despite this rising burden and the failure of most clinical trials, the ALS community remains hopeful because of the patients themselves. ALS patients are the beating heart of the ALS community. They engage in efforts to improve lives for others, raising awareness through their real-life experiences, participating in research activities, fundraising, providing samples for research, and advocating strongly in front of communities and governments to raise funds. Their engagement is highly valuable, and collaboration with the research community is essential to understanding the disease process and developing effective disease-modifying therapies. Here, we share the story of Mrs. Sherry Wityshyn, an ALS patient and a true ALS warrior from Winnipeg, Manitoba, Canada. We believe her story will inspire and motivate the entire community to learn more about ALS. Furthermore, her story gives hope to everyone impacted. In this manuscript, we also emphasize the different stages of Sherry's journey from weakness to diagnosis and our efforts to share her enduring words with policymakers in the government.

Keywords:  Amyotrophic lateral sclerosis (ALS); Canadian health; community engagement; drug discovery and development; edaravone; genetic testing; patient experience; policy makers; riluzole

DOI:  https://doi.org/10.3390/healthcare13212754
J Neurosci. 2025 Nov 12. pii: e1353252025. [Epub ahead of print]45(46):

The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.

Kathryn R Moss, Fereshteh B Darvishi, Yomna Badawi, Lauren A Fish, Jonathan R Funke, Thomas H Pedersen, Richard Robitaille, William David Arnold, Robert W Burgess, Stephen D Meriney, Hiroshi Nishimune, Smita Saxena.

  The neuromuscular junction (NMJ) is a specialized synapse essential for effective motor neuron-muscle communication and is increasingly recognized as a vulnerable site in aging and neuromuscular disease. While traditionally considered a final common pathway for motor deficits, accumulating evidence demonstrates that NMJ dysfunction is an early and critical driver of disease onset and progression in conditions such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. This review highlights shared and disease-specific mechanisms contributing to NMJ impairment, including presynaptic, postsynaptic, and perisynaptic Schwann cell defects in these diseases. We also discuss age-related changes at the NMJ, emphasizing its role in sarcopenia and muscle weakness in older adults. Furthermore, we explore emerging molecular drivers of NMJ dysfunction uncovered through studies in congenital myasthenic syndromes, autoimmune disorders, and advanced omics approaches. By integrating insights across diseases and aging, we underscore the potential for shared therapeutic strategies aimed at stabilizing NMJ function. Promising interventions targeting presynaptic neurotransmitter release, postsynaptic excitability, and perisynaptic Schwann cells are discussed as avenues to improve neuromuscular transmission and maintain muscle strength. Finally, we discuss the challenges and opportunities in translating these mechanistic insights into clinical therapies and highlight how novel human neuromuscular organoid models and advanced molecular profiling can bridge this gap. Together, these insights establish the NMJ as a critical, modifiable target for preserving motor function across neuromuscular diseases and aging.

Keywords:  Charcot–Marie–Tooth disease; aging; amyotrophic lateral sclerosis; neuromuscular disease; neuromuscular junction; neurotransmission; sarcopenia; spinal muscular atrophy

DOI:  https://doi.org/10.1523/JNEUROSCI.1353-25.2025
Neurotherapeutics. 2025 Nov 14. pii: S1878-7479(25)00271-5. [Epub ahead of print] e00793

Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS.

Francesco Liguori, Susanna Amadio, Chiara Angioli, Angelo Ferriero, Iolanda Passaro, Francesca Alberti, Fiammetta Vernì, Cinzia Volonté.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2-5 years of symptom onset. Current Food and Drug Administration-approved drugs -riluzole, edaravone, and tofersen - offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1A4V or SOD1G85R mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.

Keywords:  Amyotrophic lateral sclerosis; Clomipramine; DNA damage; Drosophila; Drug repurposing; Inflammation

DOI:  https://doi.org/10.1016/j.neurot.2025.e00793
Autophagy. 2025 Nov 10. 1-3

Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.

Gaga Kochlamazashvili, Marijn Kuijpers.

  Macroautophagy/autophagy is best known for its role in maintaining cellular homeostasis through degradation of damaged proteins and organelles. In neurons, autophagy also contributes to the regulation of activity by adjusting the availability of cellular components to physiological demand. In a recent study, we show that autophagy shapes neuronal excitability by restraining a calcium-dependent pathway that couples endoplasmic reticulum calcium release to KCNMA1/BKCa activity at the plasma membrane. When autophagy is lost, this pathway is enhanced, and seizure susceptibility increases.

Keywords:  Autophagy; BKCa; ERphagy; axon; calcium; endoplasmic reticulum; epilepsy; excitability; neuron; ryanodine receptor

DOI:  https://doi.org/10.1080/15548627.2025.2580436
Mol Neurobiol. 2025 Nov 10. 63(1): 23

CHI3L1: An Emerging Player in Neuroinflammation and Neurodegeneration.

Umar Mushtaq, Bilal Ahmad, Firdous A Khanday, Muzamil Ahmad.

  Neuroinflammation is now being identified as the major factor in the development of various neurological disorders. It is a vital process in neurons and the brain that maintains homeostasis under normal and healthy conditions. However, in hyperactivated states, neuroinflammation can also go awry when microglia and astrocytes enter a toxic, reactive state that can release chemicals that damage neurons. When innate immune cells encounter pathogens, infection, cell debris, or misfolded proteins, they release certain chemokines and cytokines to eliminate the intruding particles and protect the brain. However, persistent inflammatory reactions are harmful and can lead to neurodegeneration by continuously releasing toxic chemicals and proteins. Chitinase-3-like protein 1 (CHI3L1), a secretory protein, is emerging as a key inflammatory molecule that is strongly upregulated during neuroinflammation and has been implicated in the pathogenesis of many diseases. The brain's activated astrocytes are the main source of CHI3L1 and are a dependable biomarker for inflammatory pathologies affecting the central nervous system (CNS), including neurodegeneration and autoimmune diseases. The protein has been implicated in many neurological disorders, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and others, mediating neuroinflammation and neurodegeneration. CHI3L1 has contrasting functions in the CNS and other tissues. While the protein promotes cell proliferation and migration in various non-neuronal cancers, at the same time, it simultaneously promotes neurodegeneration and apoptosis in the CNS. This paper reviews the current developments in our knowledge of the pathogenic role of the CHI3L1 protein in various neurological disorders.

Keywords:  Alzheimer’s disease; CHI3L1; CNS; Neurodegeneration; Neuroinflammation; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-025-05354-x
Neurosci Res. 2025 Nov 08. pii: S0168-0102(25)00168-3. [Epub ahead of print] 104985

Drug discovery research with the iPSC models of neurodegenerative diseases.

Masahiro Adachi, Haruhiko Banno, Haruhisa Inoue.

  Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. Recently, it has become recognized that the use of iPSCs for screening can promote drug discovery research. Additionally, research is being conducted to develop high-quality models for drug discovery and to link translational research with clinical studies. The present work focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and broadly introduces the latest research using iPSCs, from disease mechanism studies to drug discovery research. In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI).

Keywords:  ALS with frontotemporal dementia (ALS/FTD); Alzheimer's disease (AD); amyotrophic lateral sclerosis (ALS); drug discovery research; induced pluripotent stem cells (iPSCs); neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.neures.2025.104985
Mol Neurobiol. 2025 Nov 15. 63(1): 46

The Dynamic Roles of Repressor Element 1-Silencing Transcription Factor (REST): A Double-Edged Sword in Neural Health and Disease.

Taslima Akter Eva, Avinash Shenoy, Veer B Gupta, Viswanthram Palanivel, Akanksha Salkar, Sohrab Nowroozi Nasab, Nitin Chitranshi, Mehdi Mirzaei, Yuyi You, Stuart L Graham, Devaraj Basavarajappa, Vivek Gupta.

  The repressor element 1-silencing transcription factor (REST), or neuron-restrictive silencer factor (NRSF), is crucial for gene regulation since it binds to chromatin and recruits chromatin-modifying enzymes. Acting as a regulatory hub, REST orchestrates neurogenesis, neuronal differentiation, and the preservation of neuronal identity by regulating a broad network of target genes across stem cells, non-neuronal cells, and neurons. These targets influence critical processes such as axonal growth, vesicular transport, neurotransmitter release, and ion conductance. An important feature of normal aging in cortical and hippocampal neurons is REST induction, where it contributes to extended longevity by repressing genes linked to neuronal excitability and stress vulnerability. However, REST's role in neurodegenerative diseases remains complex and context dependent. Variations in its expression and subcellular localization, including cytoplasmic translocation or loss, have been implicated in the pathology of disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and epilepsy. Given its broad regulatory functions, REST has emerged as an attractive therapeutic target. Strategies such as microRNA modulation, small molecule inhibitors, and complex-disrupting compounds have been explored, each offering unique opportunities and challenges. Understanding REST's molecular mechanisms and disease-specific functions is critical for identifying novel therapeutic interventions. This review provides a comprehensive analysis of REST's role in aging and neurodegeneration, highlighting its regulatory networks, disease relevance, and recent therapeutic strategies targeting REST, with an emphasis on their potential for clinical translation.

Keywords:  Aging; Epigenetic modification; Gene regulation; Gene repression; Neurodegenerative diseases; REST

DOI:  https://doi.org/10.1007/s12035-025-05304-7
J Extracell Vesicles. 2025 Nov;14(11): e70197

Extracellular Vesicles From Multiple Sclerosis White Matter Exhibit Synaptic, Mitochondrial, Complement and Ageing-Related Pathway Dysregulation.

Larissa Jank, Madathiparambil Kumaran Satheesh Kumar, Taekyung Ryu, Rohit Thapa, Olesia Gololobova, Timothy D Niepokny, Peter A Calabresi, Kenneth Witwer, Ranjan Dutta, Chan Hyun Na, Pavan Bhargava.

  Extracellular vesicles (EVs) are increasingly recognized as mediators of central nervous system (CNS) function and pathologies, including multiple sclerosis (MS). While plasma-derived EVs have been explored as biomarkers in MS, little is known about EVs in CNS tissue. Here, we characterize EVs from postmortem normal-appearing white matter (NAWM) of MS and control brains. EVs were separated by differential centrifugation followed by size exclusion chromatography and characterized using nanoflow cytometry, single-particle reflectance imaging sensing (SP-IRIS) and transmission electron microscopy. EV size, yield and morphology did not differ significantly between MS and control samples. Despite the small sample size (n = 4 per group), proteomic analyses revealed downregulation of synaptic and mitochondrial proteins and upregulation of complement and inflammatory proteins and pathways in MS NAWM EVs. This suggests that EVs reflect ongoing synaptic pathology, metabolic dysfunction and CNS-compartmentalized inflammation and that they may actively contribute to these pathological processes. Deconvolution analyses suggest a shift in EV cellular origin, with an increased astrocytic and decreased neuronal EV contribution in MS. Several proteomic changes we observed in CNS-derived EVs have also been reported in circulating EVs of people with MS, establishing this CNS tissue EV study as a valuable resource for identifying biomarker candidates for brain-derived plasma EV studies.

Keywords:  brain‐derived extracellular vesicles; complement activation; mitochondrial dysfunction; multiple sclerosis; normal appearing white matter; synaptic pathology; tissue‐derived extracellular vesicles

DOI:  https://doi.org/10.1002/jev2.70197
Subcell Biochem. 2026 ;110 267-286

Post-Golgi Trafficking in Plant Cells.

Elizabeth Berryman, Ariadna González Solís, Ethan Weiner, Marisa S Otegui.

  Post-Golgi trafficking in plants regulates transport to and from the cell surface, vacuolar trafficking, and recycling pathways within the endomembrane system. Endosomes serve as central hubs in these pathways, managing the composition of lipids and proteins in the plasma membrane and vacuole in response to developmental signals or environmental changes. Once internalized via endocytosis, plasma membrane proteins are directed to the trans-Golgi Network (TGN), which acts as an early endosome. From the TGN, proteins can either be sent back to the plasma membrane or trafficked to multivesicular endosomes (MVEs) for further sorting and ultimate delivery to the vacuole for degradation. Key molecular assemblies such as the retromer, the ESCRT (Endosomal Sorting Complex Required for Transport) machinery, small GTPases, adaptor proteins, and SNAREs associate with distinct domains of endosomal membranes to facilitate protein sorting and membrane remodeling. This review focuses on the roles of endosomes in post-Golgi trafficking, mechanisms of cargo sorting, and membrane remodeling.

Keywords:  Anterograde; ESCRT; Endocytosis; Endosomes; Exocytosis; Retrograde; Retromer; trans-Golgi Network

DOI:  https://doi.org/10.1007/978-3-032-06936-8_11
Trends Cell Biol. 2025 Nov 12. pii: S0962-8924(25)00249-1. [Epub ahead of print]

A STIMulating new view of activity-dependent membrane contact architecture.

Eamonn J Dickson.

  Chhikara et al. reframe stromal interaction molecule (STIM) proteins as structural organizers of membrane contact sites, not just calcium-entry activators, in neurons. STIM2 maintains resting endoplasmic reticulum (ER)-plasma membrane (PM) junctions; STIM1 dynamically expands them during neuronal activity. This activity-dependent remodeling tunes ER-PM proximity and calcium coupling, shifting focus from channel gating to spatial organization.

Keywords:  ER–PM junctions; NMDAR-dependent remodeling; STIM1/STIM2; calcium; dendritic microdomains; store-operated Ca(2+) entry (SOCE)

DOI:  https://doi.org/10.1016/j.tcb.2025.11.001
Biochem Biophys Res Commun. 2025 Nov 06. pii: S0006-291X(25)01648-1. [Epub ahead of print]791 152932

The bridge-like lipid transfer protein Vps13 are required for NVJ integrity and nucleophagy.

Tsuneyuki Takuma, Takashi Ushimaru.

  Bridge-like lipid transfer proteins (BLTPs) constitute a superfamily of proteins localized at various intracellular membrane contact sites (MCSs). Members of this family have been implicated in human neurological disorders. Among them, the BLTP Atg2 is essential for the expansion of isolation membranes in macroautophagy. In this study, we demonstrate that another BLTP, Vps13, is involved in microautophagy in budding yeast. Nucleophagy-the autophagic degradation of nuclear components-is crucial for maintaining nuclear proteostasis, and its dysfunction has been linked to neurodegenerative diseases. In micronucleophagy, a portion of the nucleus is directly engulfed by the vacuolar membrane at the nucleus-vacuole junction (NVJ), followed by degradation within the vacuole. Vps13 accumulates at the NVJ upon inactivation of the target of rapamycin complex 1 (TORC1), a process necessary for NVJ integrity. Vps13 is essential for both micronucleophagy and cell viability under nutrient-deprived conditions. Its localization to the NVJ and lipid transfer activity are both critical for nucleophagy. Taken together, these findings suggest that the bridging and lipid transfer functions of Vps13 are both required for effective nucleophagy. This study uncovers novel physiological roles of Vps13 during starvation.

Keywords:  Autophagy; NVJ; Nucleophagy; TORC1; Vps13; rDNA

DOI:  https://doi.org/10.1016/j.bbrc.2025.152932
Nat Rev Neurosci. 2025 Nov 12.

Programmed axon degeneration: mechanism, inhibition and therapeutic potential.

Andrea Loreto, Lukas J Neukomm.

Programmed axon degeneration (PAxD) is an evolutionarily conserved mechanism in the nervous system that is activated by axonal injury (axotomy) to execute the self-destruction of a severed distal axon. It can also be triggered by non-axotomy insults, resulting in the loss of axons connected to their cell bodies. PAxD is therefore a promising target for therapeutic intervention and drugs that inhibit it are currently being tested in clinical trials. In this Review, we summarize the molecular mechanism of PAxD, focusing on its regulation by nicotinamide adenine dinucleotide (NAD+) metabolism and how it dictates Ca2+-mediated axonal demise. We examine its involvement in human disease and its potential as a therapeutic target by dissecting its role in various non-axotomy disease models. Finally, we address key challenges for its clinical translation, including the need for relevant biomarkers and safety considerations. Further advancements in understanding PAxD will pave the way for new therapeutic strategies targeting human axonopathies.

DOI: https://doi.org/10.1038/s41583-025-00986-3
Neuroscience. 2025 Nov 12. pii: S0306-4522(25)01071-1. [Epub ahead of print]

Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity.

Garrett D Chavis, Pilar Rivero-Ríos, Tunahan Uygun, Takao Tsukahara, Takayuki Hayami, Grace Y Lee, Minseo Lee, Christina Pace, Francesca N Czesak, Kathryn L Hilde, Fei Li, Shigeki Iwase, Geoffrey G Murphy, Jonathan D Morrow, Huda Akil, Lois S Weisman, Michael A Sutton.

  The SNX27-Retromer and more recently discovered SNX17-Retriever complexes are key drivers in recycling internalized cargoes back to the cell surface in eukaryotic cells, but the extent to which these pathways have unique or redundant roles in neurons is not known. Here, we show similar, but non-overlapping, roles of the SNX17-Retriever and SNX27-Retromer pathways in the maintenance and plasticity of excitatory synapses. We find that in vivo disruption of either pathway in developing rats leads to a marked loss of excitatory synapses in CA1 pyramidal neurons, a phenotype that is recapitulated in cultured hippocampal neurons. Further analysis in cultured neurons confirms that SNX17 and SNX27 colocalize prominently with each other and Retriever/Retromer in early endosomes, indicating a largely shared cellular localization of the two pathways. Interestingly, coordinate disruption of both pathways produced an additive loss of excitatory synapses, suggesting parallel roles in synapse maintenance. We further show that certain cargoes are specific for each pathway and that both recycling pathways are essential for numerous forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic synaptic scaling. Together, our results support a model where the SNX17-Retriever and SNX27-Retromer pathways function largely in parallel at synapses, with their combinatorial action a key requirement for long-lasting forms of synaptic plasticity.

Keywords:  Endocytic trafficking; Protein recycling; Retriever; Retromer; Synapse; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.neuroscience.2025.11.009
Neurobiol Dis. 2025 Nov 12. pii: S0969-9961(25)00406-1. [Epub ahead of print] 107189

The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.

Victor A Streltsov, Katherine E Ganio, Stewart D Nuttall, J Andres Hernandez, Cassandra N Dennys, Peter J Crouch, Alvaro G Estevez, Maria Clara Franco, Joseph S Beckman, Blaine R Roberts.

  A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). Over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, the motor neuron disease accelerates in rodent models that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1. Previously, we have shown that the loss of zinc from SOD1 triggers motor neuron death in culture due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer showed that the zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.

Keywords:  Amyotrophic lateral sclerosis; Protein engineering; Superoxide dismutase

DOI:  https://doi.org/10.1016/j.nbd.2025.107189
Nature. 2025 Nov 12.

In situ structural mechanism of epothilone-B-induced CNS axon regeneration.

Satish Bodakuntla, Kenichiro Taira, Yurika Yamada, Pelayo Alvarez-Brecht, A King Cada, Nirakar Basnet, Rui Zhang, Antonio Martinez-Sanchez, Christian Biertümpfel, Naoko Mizuno.

Axons in the adult central nervous system (CNS) do not regenerate following injury, in contrast to neurons in the peripheral nervous system and neuronal growth during embryonic development. The molecular mechanisms that prevent regeneration of neurons in the CNS remain largely unknown1,2. Here, to address the intracellular response to injury, we developed an in situ cryo-electron tomography and cryo-electron microscopy platform to mimic axonal damage and present the structural mechanism underlying thalamic axon regeneration induced by the drug epothilone B. We observed that stabilized microtubules extend beyond the injury site, generating membrane tension and driving membrane expansion. Cryo-electron microscopy reveals the in situ structure of microtubules at 3.19 Å resolution, which engage epothilone B within the microtubule lattice at the regenerating front. During repair, tubulin clusters are delivered and incorporated into polymerizing microtubules at the regenerating site. These microtubule shoots serve as scaffolds for various types of vesicles and endoplasmic reticulum, facilitating the supply of materials necessary for axon repair until membrane tension normalizes. We demonstrate the unexpected ability of neuronal cells to adjust to strain induced by epothilone B, which creates homeostatic imbalances and activates axons to regeneration mode.

DOI: https://doi.org/10.1038/s41586-025-09654-z
Sci Rep. 2025 Nov 11. 15(1): 39434

A redox-dependent switch governing sensory axon degeneration and regeneration.

Chia-Jung Hsieh, Lauryn M Lee, Sandra Rieger.

  Zebrafish (Danio rerio) fin amputation is a widely used model for studying sensory axon degeneration and regeneration. After injury, sensory neuron terminals rapidly degenerate before regenerating. While reactive oxygen species (ROS), particularly hydrogen peroxide (H₂O₂), are known to promote axon regeneration through epidermal mechanisms, their role in degeneration remains unclear. Here, we identify mitochondrial superoxide and reactive nitrogen species (RNS), specifically peroxynitrite, as key drivers of axon fragmentation. Using AlphaFold and DeepNitro predictive modeling, we identified conserved nitration and nitrosylation sites in NMNAT rather than SARM1, two key drivers of a known axon destruction pathway, suggesting the possibility of a redox-dependent regulatory mechanism. We further explored the role of NADPH in axon degeneration since cyba mutants that do not utilize NADPH to generate ROS display delayed sensory axon degeneration. Pharmacological NADPH treatment significantly reduced amputation-induced sensory axon degeneration while enhancing regeneration. NADPH co-administration also mitigated paclitaxel-induced axon loss and improved the tactile response in a model of chemotherapy-induced peripheral neuropathy. These findings reveal a complex interplay between ROS and RNS in axon degeneration and regeneration, positioning NADPH as a promising therapeutic candidate for oxidative stress-related neurodegeneration.

Keywords:  Axon degeneration; Axon regeneration; Chemotherapy-induced peripheral neuropathy; NADPH; Nitration; Nitrosylation; Paclitaxel; Peroxynitrite; Sensory neuron

DOI:  https://doi.org/10.1038/s41598-025-23035-6
J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):

Sphingolipid and methionine metabolism in aging.

Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.

  Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.

Keywords:  Aging; Metabolism; Methionine; Sphingolipids

DOI:  https://doi.org/10.1242/jcs.264026
Int J Biol Sci. 2025 ;21(14): 6234-6251

Generation of Human 3D Airway Assembloids for Advanced Modeling.

Maria Chiara Iachini, Alberto Coglot, Dorian Tace, Noemi Elia, Francesco Rusconi, Federica Cosentino, Gianluca Lopez, Mariacristina Crosti, Tuğba Dursun Usal, Edoardo Scarpa, Antonio D'Amore, Vitale Miceli, Lorenzo Rosso, Lorenza Lazzari.

  The development of physiologically relevant in vitro 3D models is crucial for studying lung biology and disease mechanisms. While airway organoids have significantly improved our ability to mimic lung tissue, they lack key nonepithelial components that are essential for tissue homeostasis. Here, we describe the generation of human airway assembloids, combining airway organoids, stromal fibroblasts, and endothelial cells to better replicate the native lung environment. The model was generated from healthy lung tissue donors by using a scaffold-free culture system to promote cell self-organization. Assembloids exhibited long-term viability, maintained typical airway epithelial markers, and demonstrated functional characteristics, such as mucus production and ciliary beating. This technology provides a powerful platform for studying airway physiology, disease mechanisms, and therapeutic approaches, with potential applications in regenerative and personalized medicine. Our study established a novel, reproducible 3D assembloid model of the human airways, bridging the gap between traditional organoid cultures and complex tissue engineering strategies.

Keywords:  3D model; airway; assembloids; lung; organoids

DOI:  https://doi.org/10.7150/ijbs.113920