bims-axbals 2026-02-08 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–02–08
24 papers selected by
TJ Krzystek

TBK1 activity regulates the directionality of axonal transport of signalling endosomes.
Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD.
Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes.
FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.
Mutant TDP-43 drives impairments in axonal transport and glycolysis in a mouse stem-cell-derived motor neuron model of amyotrophic lateral sclerosis (ALS).
Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.
Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.
Early Reprogramming Intermediates Enable Direct Neuronal Conversion Via NGN2.
Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes.
Axonal dying back of upper motor neurons in human ALS.
Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP+ Model of Parkinson's Disease.
Proteostasis of organelles in aging and disease.
Pinpointing protein as the problem.
Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice.
Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions.
LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal toxicity via phosphorylation within its lipid-sensing ALPS2 motif.
Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development.
Extracellular Vesicle-Mediated Delivery of Constrained Peptides Disrupts the Pathogenic Interaction of LRRK2-FADD in Parkinson's Disease.
Spatial organization of ER-derived protein aggregates in the nucleus requires the Hsp70-family member BiP.
The HCF-1:OGT axis regulates neuronal proliferation and differentiation.
Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.
Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations.
Altered Neuronal Architecture in Induced Pluripotent Stem Cells-Derived Neurons from Patients with Schizophrenia Harboring CNTNAP2 Deletion.
Patient-derived neural organoids reveal developmental impairments associated with a novel GJB1 mutation in X-linked Charcot-Marie-Tooth disease.

Life Sci Alliance. 2026 Apr;pii: e202503527. [Epub ahead of print]9(4):

TBK1 activity regulates the directionality of axonal transport of signalling endosomes.

David Villarroel-Campos, Jose Norberto S Vargas, Martin Wallace, Kai Sun, James N Sleigh, Pietro Fratta, Giampietro Schiavo.

The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.

DOI: https://doi.org/10.26508/lsa.202503527
iScience. 2026 Feb 20. 29(2): 114596

Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD.

Ling Lian, Hayley Robinson, Noah Daniels, G Aleph Prieto, Gunnar H D Poplawski, Rodrigo Lopez-Gonzalez.

  The C9orf72 hexanucleotide repeat expansion (G4C2) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet targeted therapies remain unavailable. Here, we show that induced pluripotent stem cell (iPSC)-derived post-mitotic neurons from C9orf72 carriers exhibit age-dependent cell-cycle reentry, increased S-phase entry, and elevated cyclin and CDK expression. Mechanistically, arginine-containing dipeptide repeat proteins (poly-GR and poly-PR) translated from G4C2 repeats drive this aberrant activation through stimulation of the CDK4/6 pathway, whereas poly-GP and C9orf72 loss-of-function show no effect. Importantly, the FDA-approved CDK4/6 inhibitor palbociclib normalizes cell-cycle progression, reduces S-phase entry, decreases motor neuron death, and restores synaptic proteins PSD95 and synapsin-1. Single-nucleus RNA sequencing from C9orf72 patient cortex reveals cell-cycle activation within excitatory neuron subclusters and alterations in DNA repair and cell-cycle regulation pathways, supporting our in vitro findings. These findings establish cell-cycle dysregulation as a central pathogenic mechanism in C9orf72 ALS/FTD and highlight CDK4/6 signaling as a promising therapeutic target.

Keywords:  Cellular neuroscience; Clinical neuroscience; Health sciences; Neuroscience; Pharmaceutical science

DOI:  https://doi.org/10.1016/j.isci.2025.114596
Science. 2026 Feb 05. 391(6785): eadv2600

Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes.

Xin Jiang, Laure Schaeffer, Divya Patni, Tommaso Russo, Chao-Zong Lee, Corey Aguilar, Christine Marques, Karen Jansen-West, Marian Hruska-Plochan, Ananya Ray-Soni, Su Min Lim, Aaron Held, Mei Yue, Paula Castellanos Otero, Sandeep Aryal, Hortense D A M Beaussant, Himanish Basu, Hiro Takakuwa, Lillian M Daughrity, Nandini Ramesh, Paulo Da Costa, Ana Rita A A Quadros, Matthew Nolan, Charles Jourdan F Reyes, Hayden Wheeler, Laura C Moran, Grant Griesman, Benjamin Wymann, Bianca A Trombetta, Emma Sofia Lopez-De-Silanes, Michael Canori, Gopinath Krishnan, Yasmim Vieira Souza Da Silva, Gilbert Eriani, Mark W Albers, Steven E Arnold, Yuyu Song, Ankur Jain, Isaac M Chiu, Yong-Jie Zhang, Fen-Biao Gao, Brian J Wainger, Magdalini Polymenidou, Leonard Petrucelli, Franck Martin, Clotilde Lagier-Tourenne.

GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell-derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.

DOI: https://doi.org/10.1126/science.adv2600
BMC Biol. 2026 Feb 06.

FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.

Donovan W McDonald, Nikita Chugh, Rares Sava, Martin L Duennwald.

   BACKGROUND: Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models.
RESULTS: Using optimized low-expression FUS and TDP-43 yeast models, we demonstrate that chronological ageing antagonizes proteostasis, the steady state levels and solubility of molecular chaperones, and aggregation of FUS and TDP-43. In addition, mistranslation caused by tRNA variants further antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity.
CONCLUSIONS: Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.

Keywords:  ALS; Ageing; FUS; Mistranslation; Mitochondria; Molecular chaperone; Protein aggregation; Protein misfolding; TDP-43

DOI:  https://doi.org/10.1186/s12915-026-02537-3
Cell Death Dis. 2026 Jan 31. 17(1): 193

Mutant TDP-43 drives impairments in axonal transport and glycolysis in a mouse stem-cell-derived motor neuron model of amyotrophic lateral sclerosis (ALS).

Emily Carroll, Jakub Scaber, Iris-Stefania Pasniceanu, Ruxandra Dafinca, David Gordon, Ana Candalija, Kevin Talbot.

TDP-43 dysfunction is thought to be central to ALS pathogenesis. Studying mutations in the gene which encodes TDP-43, TARDBP, provides a valuable opportunity to gain insight into how TDP-43 dysfunction alters cellular homoeostasis. Our group has previously developed a TDP-43M337V mouse embryonic stem cell-derived motor neuron (mESC-MN) model, which expresses a single copy of the human TARDBP gene expressing the pathogenic M337V mutation at low levels. Here, we perform extensive phenotypic characterisation of this model, and show that TDP-43M337V leads to reduced MN viability, impaired axonal transport and reduced basal glycolysis compared to TDP-43WT controls. Altered neuronal viability and function occurs in the absence of TDP-43 mislocalisation or aggregation, suggesting 'proteinopathy' is downstream of these ALS-relevant phenotypes. These findings provide further support for a link between TDP-43 dyshomeostasis, cellular bioenergetics and axonal transport and suggest these pathways warrant further investigation as targets for therapeutic intervention.

DOI: https://doi.org/10.1038/s41419-026-08437-2
Neurobiol Dis. 2026 Feb 04. pii: S0969-9961(26)00053-7. [Epub ahead of print] 107309

Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.

Brianna Hnath, Srinivasan Ekambaram, Nikolay V Dokholyan.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2-3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.

Keywords:  ALS; Aggregation; Extracellular vesicles; Oligomer; SOD1; Spreading

DOI:  https://doi.org/10.1016/j.nbd.2026.107309
Neural Regen Res. 2026 Feb 05.

Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.

Suzy Varderidou-Minasian, Channa E Jakobs, Svetlana Pasteuning-Vuhman, Lars Gal, Annabel Timmers, Maarten Altelaar, Magdalena J Lorenowicz, R Jeroen Pasterkamp.

   ABSTRACT: Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell-derived motor neurons carrying amyotrophic lateral sclerosis-associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell-derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell-derived extracellular vesicles as a versatile therapeutic approach.

Keywords:  C9ORF72; FUS; amyotrophic lateral sclerosis; extracellular vesicles; induced pluripotent stem cells; mesenchymal stromal/stem cells; motor neurons; proteomics; transactive response (TAR) DNA-binding protein 43 (TDP-43)

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01790
J Mol Neurosci. 2026 Feb 03. 76(1): 20

Early Reprogramming Intermediates Enable Direct Neuronal Conversion Via NGN2.

Silvia Angiolillo, Wei Qin, Alessia Gesualdo, Roberta Frison, Nicola Elvassore, Cecilia Laterza, Onelia Gagliano.

  The generation of engineered neurons via Neurogenin-2 (NGN2) overexpression, starting from human induced pluripotent stem cells (hiPSCs), is a powerful tool for modeling neurological diseases. However, using stabilized hiPSCs as a starting point significantly increases the time required to obtain a valuable human neuronal model in vitro. Here, we demonstrated that as little as 3 days of transient expression of reprogramming factors in human fibroblasts can unlock the ability of these cells to transdifferentiate into neurons upon overexpression of NGN2. We used single-cell transcriptomic data to dissect the distinct cell identities that emerge during reprogramming. We identified three distinct reprogramming intermediate populations responsive to NGN2-mediated neuronal induction and found that partial reprogramming for only 3 days is sufficient to mediate NGN2 neuronal conversion of human fibroblasts. Moreover, we found that the efficiency in neuronal fate acquisition mediated by NGN2 overexpression is strictly correlated with the stage of reprogramming used as a starting point.

Keywords:  IPSC direct conversion; Induced neurons; NGN2; Neural differentiation; Reprogramming intermediate; Transient reprogramming-programming

DOI:  https://doi.org/10.1007/s12031-025-02460-2
bioRxiv. 2026 Jan 19. pii: 2026.01.17.700056. [Epub ahead of print]

Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes.

Delong Li, Wenxin Zhang, Michaela Medina, Jan F M Stuke, Andre Schwarz, Jonas Brill, Johann Brenner, Felix Kraus, Simon Ohlerich, Javier Lizarrondo, Jeremy Pflaum, Julia H Grass, Lena-Marie Soltow, Dietmar Hammerschmid, Natalie Weber, Sonja Welsch, Julian D Langer, Maike Windbergs, J Wade Harper, Erin Schuman, Gerhard Hummer, Danielle A Grotjahn, Florian Wilfling.

Lysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester (LLOMe) is widely used to model lysosomal damage, yet its mechanism remains poorly understood. The prevailing view holds that LLOMe polymerizes into membrane-permeabilizing peptide chains within the lysosomal lumen. Using cryo-electron tomography in cultured cells and primary neurons, we visualized the structural basis of LLOMe-induced lysosomal damage. We reveal that LLOMe forms amyloid structures within lysosomes that directly interact with and rupture the limiting membrane through mechanical stress. In vitro reconstitution confirms this amyloid-mediated mechanism. These findings establish a structural paradigm for lysosomal membrane disruption and provide insights into how disease-relevant protein aggregates, implicated in neurodegeneration and LSD, may compromise lysosomal integrity.

DOI: https://doi.org/10.64898/2026.01.17.700056
Res Sq. 2026 Jan 12. pii: rs.3.rs-8545414. [Epub ahead of print]

Axonal dying back of upper motor neurons in human ALS.

Haley Cropper, Fozia Mir, Jianguo Liu, Vidushi Srivastava, Mohammed Ramizuddin, Kylie Kopecky, Ebony Mocanu, Fabien Dachet, Qin Li Jiang, Madhu Soni, Tibor Valyi-Nagy, Diana Mnatsakanova, Charles Abrams, Fei Song, Jeffrey Loeb.

Patients with amyotrophic lateral sclerosis (ALS) present with arm, leg, or bulbar weakness with or without spasticity. While genetics plays a clear role in a subset of cases, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. Here, we examined the clinicopathological relationships between UMN and LMN disease in ten ALS patients. Detailed clinical assessments were obtained and tissues from the motor cortex, brainstem, and spinal cord were collected via a rapid autopsy protocol. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43. Total RNA-sequencing was performed in the medulla, cervical, and lumbar spinal cords from each patient to identify pathways enriched at sites of disease onset. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and spasticity, indicating both UMN and LMN involvement. Postmortem examination showed LMN degeneration and microglial activation were highest at sites of disease onset. In contrast, UMN degeneration of the corticospinal tract (CST) was present equally at all levels of the spinal cord up through the medulla, regardless of the site of disease onset. Surprisingly, there was no evidence of UMN degeneration of cortical motor neurons or their projecting axons above the brainstem. Similarly, while extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. Mechanistically, RNA-sequencing implicated inflammatory pathways, especially at sites of disease onset. Our findings suggest that many ALS patients without FTD have a dying back of UMN axons, independent of the site of disease onset, which stops in the brainstem with preservation of cortical motor neurons and their proximal axons. Our findings suggest that UMN axonal degeneration can be directly triggered by LMN degeneration and inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-8545414/v1
J Neurochem. 2026 Feb;170(2): e70363

Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP+ Model of Parkinson's Disease.

Hyun-Seung Lee, Sun-Ah Kang, Jae-Won Eom, Min Seong Kim, Ji-Soo Kim, Yang-Hee Kim.

  Dysregulation of autophagy and lysosomal function is central to Parkinson's disease (PD), yet the upstream mechanisms leading to lysosomal failure remain unclear. Across primary mouse cortical neurons, MT-3 deficient primary mouse astrocytes, human iPSC-derived midbrain dopaminergic neurons, and Rho0 CHO cells lacking mitochondrial respiration, we investigated how mitochondrial stress perturbs zinc (Zn2+) homeostasis and lysosomal integrity. We identify intracellular zinc as a critical mediator linking mitochondrial dysfunction to lysosomal membrane permeabilization (LMP) and neuronal death. Inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP+) elevated reactive oxygen species (ROS) and intracellular zinc, jointly driving LMP. Blocking either ROS or zinc markedly attenuated lysosomal damage and cell death, demonstrating that both act upstream of LMP. To define zinc regulation, we examined metallothionein-3 (MT-3), a brain-enriched zinc-binding protein. MT-3-deficient astrocytes were more vulnerable to MPP+ and zinc overload (ZnCl2) but paradoxically resistant to hydrogen peroxide (H2O2), suggesting that MT-3 buffers cytosolic zinc during mitochondrial injury or extracellular zinc influx yet can release bound zinc under oxidative conditions. Using Rho0 cells, we show that MPP+ toxicity depends on mitochondrial ROS, as loss of mitochondrial function nearly abolished cell death. However, Rho0 cells were highly sensitive to ZnCl2 and H2O2 and exhibited markedly reduced lysosomal abundance, indicating limited capacity to sequester zinc and increased susceptibility to zinc-mediated injury. These findings support a coordinated system in which lysosomes and zinc-binding proteins maintain zinc homeostasis. When cytosolic zinc rises, its accumulation within lysosomes induces LMP and accelerates cell death. Collectively, our results identify intracellular zinc as an upstream trigger of lysosomal dysfunction and neurodegeneration. Zinc-mediated LMP provides a mechanistic link between mitochondrial injury, impaired autophagic flux, and α-synuclein pathology in PD. Enhancing zinc homeostasis and lysosomal resilience may offer promising therapeutic strategies.

Keywords:  Parkinson's disease; lysosomal membrane permeabilization (LMP); mitochondria; reactive oxygen species (ROS); zinc

DOI:  https://doi.org/10.1111/jnc.70363
FEBS J. 2026 Feb 04.

Proteostasis of organelles in aging and disease.

Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.

  To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.

Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules

DOI:  https://doi.org/10.1111/febs.70439
Science. 2026 Feb 05. 391(6785): 555-556

Pinpointing protein as the problem.

Frederick J Arnold, Albert R La Spada.

A genetic repeat expansion linked to two neurodegenerative disorders harms neurons through toxic proteins, not RNA.

DOI: https://doi.org/10.1126/science.aee6924
bioRxiv. 2026 Jan 13. pii: 2026.01.13.699312. [Epub ahead of print]

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice.

Hayk Davtyan, Sarah Naguib, Yuliya Voskobiynyk, Jean Paul Chadarevian, Joia K Capocchi, Jeannie L Giacchino, Ghazaleh Eskandari-Sedighi, Vivianna DeNittis, Jeremy B Ford, Ani Agababian, Jasmine Nguyen, Alina L Chadarevian, Madison S Sutherland, Sepideh Kiani Shabestari, Alissa L Nana, Jiasheng Zhang, Salvatore Spina, Man Ying Wong, Lea T Grinberg, William W Seeley, Eric Huang, Claire D Clelland, Shiaoching Gong, Li Fan, Jeanne T Paz, Mathew Blurton-Jones, Li Gan.

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglia (iMG) into progranulin ( Grn )-deficient mice. We find that wild-type, but not Grn -deficient, human iMG restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.
One Sentence Summary: Our study demonstrates that xenotransplantation of wild-type human iPSC-derived microglia into progranulin-deficient mice mitigates core neuropathological, network-level, and behavioral features of Frontotemporal Dementia.

DOI: https://doi.org/10.64898/2026.01.13.699312
Neural Regen Res. 2026 Jan 27.

Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions.

Jingjing Liu, Lijun Zhou, Youqing Deng, Renshi Xu.

   ABSTRACT: Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease that targets motor neurons in the cerebral cortex, medulla oblongata, and spinal cord. This review focuses on the current concepts in the aetiopathogenesis and diagnosis of amyotrophic lateral sclerosis, aiming to explore potential neural repair strategies (curative and/or progression-retarding therapeutics). Recent studies have highlighted that the complex pathogenesis of amyotrophic lateral sclerosis is related to its multifactorial aetiology, including proteostasis disruption, impaired RNA metabolism and DNA repair, cytoskeletal and axonal transport defects, excitotoxicity, neuroinflammation, mitochondrial dysfunction, oligodendrocyte dysfunction, nucleocytoplasmic transport deficits, lipid dyshomeostasis, and autophagy. Several approved drugs are currently used to treat patients with amyotrophic lateral sclerosis; however, their curative efficacy is limited. Thus, the search for effective therapeutic strategies for amyotrophic lateral sclerosis requires a comprehensive understanding of its pathogenesis. Current evidence indicates that a single drug cannot provide a satisfactory therapeutic effect. Additionally, multiple pathophysiological processes and related targets are involved in the pathogenesis of amyotrophic lateral sclerosis. Therefore, research on multi-target synchronous interventions may be the path forward for discovering and developing potential neural repair strategies.

Keywords:  RNA; amyotrophic lateral sclerosis; axonal transport; endoplasmic reticulum stress; excitatory amino acids; lipid metabolism; mitochondrial dysfunction; neuroinflammation; oxidative stress; protein aggregates

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00221
bioRxiv. 2026 Jan 13. pii: 2026.01.12.699049. [Epub ahead of print]

LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal toxicity via phosphorylation within its lipid-sensing ALPS2 motif.

Md Shariful Islam, Valentin Cóppola-Segovia, Alessandra Musso, Darren J Moore.

Mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing a Roc GTPase domain and a serine/threonine-directed protein kinase domain, with PD-linked mutations known to enhance LRRK2 kinase activity and neuronal toxicity. Our previous studies identified the Golgi protein, ADP-Ribosylation Factor GTPase-Activating Protein 1 (ArfGAP1), as a novel modifier of LRRK2-induced cellular toxicity, where it can serve as a GAP-like protein and a robust kinase substrate of LRRK2. Here, we further explore the phosphorylation of ArfGAP1 by LRRK2 and its functional consequences. LRRK2 mediates the robust phosphorylation of ArfGAP1 within its lipid-sensing ALPS2 motif at residues Ser284, Thr291 and Thr292. We mutated these three phosphorylation sites, either alone or combined, to create hydrophobic phospho-null or charged phospho-mimicking versions of ArfGAP1. We find that modulating ArfGAP1 phosphorylation impairs its normal capacity to induce Golgi fragmentation upon overexpression in neural cells. Blocking phosphorylation impairs ArfGAP1-induced neurite outgrowth inhibition in primary neurons and protects against the neurotoxic effects of PD-linked G2019S LRRK2. ArfGAP1 interactome analysis in neural cells identifies 114 putative interacting proteins with a proportion of these unexpectedly localized to mitochondria, including the outer membrane proteins Voltage-Dependent Anion Channel (VDAC) 1-3. An ArfGAP1 triple phospho-mimic displays an increased interaction with mitochondrial VDACs owing to the redistribution of ArfGAP1 from the cis -Golgi to the cytoplasm. Promoting ArfGAP1 phosphorylation also blocks the formation of Golgi-derived vesicles following mild ER stress. Our data provides evidence for a complex functional interaction between LRRK2 and ArfGAP1 that serves to regulate ArfGAP1 subcellular localization, protein interactions, activity and neuronal toxicity via LRRK2-mediated phosphorylation of its membrane-binding ALPS2 motif. Our findings support additional validation of ArfGAP1 as a putative therapeutic target for modulating LRRK2 -linked PD.

DOI: https://doi.org/10.64898/2026.01.12.699049
bioRxiv. 2026 Jan 14. pii: 2026.01.14.699478. [Epub ahead of print]

Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development.

Jayne Aiken, Carris Borland, Nicolas Marotta, Benjamin L Prosser, Erika L F Holzbaur.

The nervous system relies on billions of neurons connected through trillions of synapses to support a vast array of vital functions. Despite the critical importance of this synaptic network, the cellular mechanisms dictating synapse formation during human neurodevelopment remain unclear. Long-distance trafficking of synaptic components is critical for both synaptogenesis and the maintenance of synaptic function across lifespan. The microtubule motor KIF1A has a highly conserved role in the trafficking of synaptic vesicle precursors, while mutations in KIF1A are causal for the neurodevelopmental and neurodegenerative disease KIF1A -Associated Neurological Disorder (KAND). Here, we employ isogenic human induced pluripotent stem cells (iPSCs) gene-edited to express pathogenic KIF1A variants to assess how disparate mutations alter synaptic trafficking and function. We compared the effects of both loss-of-function and gain-of-function mutations on KIF1A motor activity. We found that both null (p.C92*) and hypoactive (p.P305L) mutations induce delayed neurite outgrowth, mislocalization of synaptic cargos, and decreased synapse density. Conversely, the hyperactive KIF1A mutation (p.R350G) supports neurite outgrowth but leads to aberrant motility of synaptic vesicle precursors along the axon. Further, live imaging reveals that hyperactive KIF1A induces deficits in the microtubule-dependent patterning of presynaptic components along the developing axon, suggesting a failure to respond to cytoskeletal cues directing cargo delivery. Functional analysis of neuronal activity via multi-electrode arrays reveals delayed synaptic maturation in loss-of-function mutations (p.P305L, p.C92*). In contrast, the hyperactive p.R350G mutation exhibits accelerated activity maturation and possible excitotoxicity. Together, these data provide insights detailing how pathogenic variants in KIF1A causative for KAND exhibit distinct effects at the molecular level that lead to significant downstream deficits in synaptic function in human neurons.

DOI: https://doi.org/10.64898/2026.01.14.699478
J Extracell Biol. 2026 Feb;5(2): e70116

Extracellular Vesicle-Mediated Delivery of Constrained Peptides Disrupts the Pathogenic Interaction of LRRK2-FADD in Parkinson's Disease.

Yaochao Zheng, Brian Joseph Jurgielewicz, Leah G Helton, Hardy J Rideout, Eileen J Kennedy, Steven L Stice, Yao Yao.

  The interaction between mutated leucine-rich repeat kinase 2 (LRRK2) and the death adaptor protein FADD accounts for apoptotic death of dopaminergic neurons in familial Parkinson's disease (PD) driven by LRRK2 mutations. Disrupting this pathogenic interaction using constrained peptides is a promising therapeutic strategy to mitigate apoptotic neuronal death in PD. However, efficiently delivering these therapeutic peptides to disease-relevant cells within the central nervous system (CNS) remains challenging due to degradation in circulation and poor blood-brain barrier and cell membrane penetration. Here, we present a strategy to use extracellular vesicles (EVs) as delivery vehicles for the therapeutic peptides to enhance their cellular uptake and CNS targeting. Following an optimized passive loading approach, we successfully packaged these peptides into EVs, improving their cellular uptake by disease-relevant neural cells in vitro and brain biodistribution in mice following intravenous administration. EV-based delivery enhanced the therapeutic efficacy of these peptides in disrupting FADD-LRRK2 interactions, reducing downstream caspase signaling and neuronal death in cellular models of PD compared to the free peptide format. These findings support the use of EVs as a promising shuttle for peptide-based therapies in PD and potentially other neurological disorders.

Keywords:  LRRK2; Parkinson's disease; blood‐brain barrier; drug delivery; extracellular vesicle; therapeutic peptide

DOI:  https://doi.org/10.1002/jex2.70116
Biochem Biophys Res Commun. 2026 Feb 04. pii: S0006-291X(26)00170-1. [Epub ahead of print]805 153406

Spatial organization of ER-derived protein aggregates in the nucleus requires the Hsp70-family member BiP.

Shoukang Du, Yuhan Wang, Ting Gang Chew.

  Cells maintain proteostasis by sequestering misfolded proteins into deposition sites. Aggregation-prone endoplasmic reticulum (ER) proteins form membrane-bound nuclear compartments that are cleared during cell division, yet the mechanisms underlying their spatial organization remain unclear. Here, using transcriptomic and proteomic analyses, we identified the ER-localized Hsp70 chaperone BiP as a key player. Genetic depletion or chemical inhibition of BiP prevented nuclear aggregate formation, while manipulating BiP regulators perturbed the aggregate formation. BiP-driven aggregation precedes the inner nuclear membrane synthesis that encapsulated the aggregates. Under proteostatic stress, nuclear aggregates localized adjacent to ER-derived aggregates. Our findings demonstrate that BiP is essential for organizing ER-derived aggregates in the nucleus, which further regulate nuclear proteostasis through spatial interactions with nuclear aggregates.

Keywords:  BiP; Endoplasmic reticulum; Nucleus; Protein aggregates; Proteostasis

DOI:  https://doi.org/10.1016/j.bbrc.2026.153406
Neurobiol Dis. 2026 Feb 04. pii: S0969-9961(26)00052-5. [Epub ahead of print] 107308

The HCF-1:OGT axis regulates neuronal proliferation and differentiation.

Ayushma, Priyanka Prakash Srivastava, Shruti Kaushal, Jaspreet K Dhanjal, Vaibhav Kapuria, Shilpi Minocha.

  Neuronal differentiation requires precise coordination of progenitor proliferation, lineage commitment, and chromatin regulation to establish functional brain architecture. Host Cell Factor-1 (HCF-1), an X-linked transcriptional co-regulator linked to human intellectual disability, is essential for early development, yet its lineage-specific roles during mammalian neurogenesis remain incompletely defined. Here, we investigate the function of the HCF-1-OGT axis during neuronal differentiation and forebrain development. Early embryonic loss of HCF-1 resulted in developmental arrest due to gastrulation defects, while conditional deletion in Nkx2.1-derived neuronal lineages caused pronounced cortical disorganization, reduced GABAergic interneuron survival, and severe defects in forebrain commissures, including the corpus callosum and anterior commissure. These abnormalities were not observed following glial-restricted deletion, indicating a neuron-specific requirement for HCF-1. Neuronal ablation alone did not phenocopy these defects; however, combined neuronal ablation and HCF-1 loss exacerbated cortical and commissural abnormalities, revealing increased neuronal vulnerability. Transcriptomic profiling following HCF-1 depletion identified widespread dysregulation of gene networks associated with neuronal differentiation, synaptic organization, chromatin regulation, and axon guidance. Consistently, HCF-1 directly occupied promoters of key neuronal genes, including Elavl3 and NeuroD1, and its loss reduced activating chromatin marks at these loci. In vitro, depletion of HCF-1 or inhibition of OGT impaired neuronal proliferation, differentiation, and neurite outgrowth. Glycoproteomic analysis further revealed disruption of OGT-dependent protein networks involved in neuronal structure and maturation. Together, these findings identify HCF-1 as a central regulator of neuronal differentiation and forebrain organization and provide mechanistic insight into how disruption of the HCF-1-OGT axis contributes to neurodevelopmental disorders.

Keywords:  Differentiation; HCF-1; Host cell factor 1; Neurons; Nkx2.1; O-linked N-acetylglucosamine transferase; OGT

DOI:  https://doi.org/10.1016/j.nbd.2026.107308
J Physiol. 2026 Feb 03.

Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.

Andrea Telek, Ivett Gabriella Szabó, Anikó Keller-Pintér, Mónika Gönczi, Eliza Guti, László Szabó, Brigitta Tillmann, Zoltán Márton Kohler, László Juhász, Péter Bai, Szilárd Póliska, Zsuzsanna Gaál, László Csernoch, János Fodor.

  Mitochondria are dynamic organelles that undergo fusion and fission. Key proteins are needed to create mitochondrial networks, as well as facilitate biogenesis, fragmentation or movement within the cell. Septins are considered as the fourth component of the cytoskeleton, providing attachment sites for proteins. Besides that, they have important roles in different cellular processes, including mitochondrial fission and fusion (remodelling). Septins form oligomeric complexes comprising various septin subgroups, which can create higher-order structures. Septin7 is the sole member of its subgroup. We aimed to examine how mitochondrial dynamics and oxidative phosphorylation (OXPHOS) are affected in Septin7 downregulated C2C12 (S7-KD) myoblasts and terminally differentiated myotubes compared to scrambled short hairpin RNA-transfected control cells. We detected altered expression of genes related to mitochondrial biogenesis (PGC1α), dynamics (DRP1, OPA1 and MFN2) and autophagy (PINK1 and BNIP3); furthermore, a significant decrease in differentiation-dependent mRNA expression of OXPHOS markers (ATP synthase, COX1 and SDH). Septin7 downregulation also affected the expression of post-translational modifications of MFN2 and DRP1. Functional measurements of OXPHOS revealed decreased O2 consumption (flux) and higher O2 concentration in Septin7 KD cultures following selective inhibition of electron transport complexes. We observed significant alterations in basal respiration and OXPHOS pathways in Septin7 KD cultures. Our results suggest that Septin7, as a cytoskeletal protein, could be a significant regulator of mitochondrial dynamics and oxidative metabolism. Therefore, these molecules, as mitochondrial dynamics modulators, can serve as potential therapeutic targets in diseases related to changes in mitochondrial function. KEY POINTS: Knockdown of Septin7 results in altered gene and protein expression of markers controlling mitochondrial dynamics. Diminished level of Septin7 causes decreased gene expression of members of oxidative phosphorylation. Knockdown of Septin7 has an impact on microRNAs involved in the regulation of mitochondrial markers. Septin7 has an impact on mitochondrial respiration.

Keywords:  electron transport; mitochondria; remodelling; septin; skeletal muscle

DOI:  https://doi.org/10.1113/JP288715
bioRxiv. 2026 Jan 22. pii: 2026.01.20.697254. [Epub ahead of print]

Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations.

Vipin Kumar, Victor M Sanchez Franco, Faith S Ferry, Yizhou Xie, Anelise N Hutson, Yutian J Zhang, Skylar D Daniels, Dieu Linh Nguyen, Lucia K Spera, Eleanora M Snyder, Anneke Knauss, Srilakshiya L Sudhakar, Grace Y Duan, Elizabeth M Paul, Masashi Tabuchi.

Microscale biophysical alterations in neuronal dynamics can have profound implications for macroscale pathological outcomes in the brain. Despite the critical need to link neuronal perturbations to large-scale disease manifestations, few studies successfully bridge these hierarchical scales. Here, we bridge microscale biophysical variability within neuronal dynamics to macroscale disease-related phenotypes. We find that Drosophila models expressing tauopathy- and epilepsy-associated molecular mutations exhibit increased dynamic instability in the timing of action potential initiation, and microscale biophysical changes are manifested at the level of the macroscale global brain state. We show that variability in voltage-gated sodium channel currents during non-stationary channel inactivation may act as a microscale biophysical contributor to the increased dynamic instability observed in action potential timing. We also find that treatment with antiepileptic drugs stabilizes neuronal dynamics by modulating this variability in voltage-gated sodium channel currents. Finally, we show that neurons derived from human induced pluripotent stem cells (iPSCs) from patients with Alzheimer's disease and epilepsy exhibit analogous dynamic instability, which is reversible by administration of antiepileptic medications. Our results highlight how subtle microscale neuronal instabilities propagate and are amplified to produce macroscopic pathological phenotypes, providing new biophysical insights into neurological disorders and potential strategies for therapeutic intervention.
Significance Statement: Linking microscale neuronal changes to macroscale disease phenotypes remains a key challenge in neuroscience biophysics. Here, we show that subtle biophysical instability, such as variability in action potential timing and increased noise in voltage-gated sodium channel activity, can destabilize neuronal network integrity and cause systemic pathology. Stabilizing neuronal dynamics with antiepileptic drugs reverses tau-induced instabilities in a Drosophila disease model. Similar neuronal instabilities occur in fly neurons expressing epilepsy-linked sodium channel mutations and in human iPSC-derived neurons from Alzheimer's and epilepsy patients, revealing a shared cellular mechanism. These findings highlight that targeting microscale instabilities may offer a unifying therapeutic approach for complex neurological disorders.

DOI: https://doi.org/10.64898/2026.01.20.697254
Stem Cells Dev. 2026 Feb;35(3-4): 67-79

Altered Neuronal Architecture in Induced Pluripotent Stem Cells-Derived Neurons from Patients with Schizophrenia Harboring CNTNAP2 Deletion.

Bipin Raj Shekhar, Shyla R Menon, Shailesh Pande, Dhanjit K Das.

  Schizophrenia, a complex neuropsychiatric disorder, exhibits a wide range of genetic diversity. Multiple Genome-Wide Association Studies have identified several Copy Number Variations (CNVs) associated with schizophrenia. One of the significant CNVs, comprising an intragenic deletion of the CNTNAP2 gene, has been associated with various neuro-developmental and neuro-psychiatric disorders. However, the molecular mechanism leading to the pathogenesis of schizophrenia remained unclear. In this study, we report a 7q35-36.1del encompassing the entire CNTNAP2 gene in two affected siblings. Human induced Pluripotent Stem Cells (hiPSCs) were generated from both affected individuals. Neurons derived from the patient's hiPSCs lines have revealed that the dendritic length and arborization, spine number and density, soma area and volume were decreased in the patient's neurons, while axon length was increased. Further classifying the dendritic spines, it was observed that the percentage of filopodia spines was increased, whereas stubby, mushroom, and long thin spines were decreased in the patient's neurons. Transcriptomics of hiPSCs-derived neurons has revealed eight significantly dysregulated genes that interact directly or indirectly with CNTNAP2. Of these eight genes, schizophrenia-associated genes, PADI2 and LHX2, were observed to be significantly dysregulated. Overall, this study has identified abnormalities in neuronal architecture in hiPSCs-derived patients' neurons harboring CNTNAP2 gene deletion, confirming the disease pathophysiology of schizophrenia.

Keywords:  CNTNAP2 gene; dendritic arborization; dendritic spine; hiPSCs; neuronal defects; schizophrenia

DOI:  https://doi.org/10.1177/15473287251413992
Neurobiol Dis. 2026 Jan 31. pii: S0969-9961(26)00043-4. [Epub ahead of print] 107299

Patient-derived neural organoids reveal developmental impairments associated with a novel GJB1 mutation in X-linked Charcot-Marie-Tooth disease.

Jianying Guo, Qianhui Lee, Hui Qiu, Yuan Wei, Xiaohui Zhu, Liying Yan, Jie Na.

  Charcot-Marie-Tooth disease (CMT) is one of the most prevalent inherited peripheral neuropathies. CMT type X1 (CMTX1), caused by mutations in GJB1 gene, represents the most common X-linked subtype with central nervous system (CNS) involvement. Here, we report the identification and functional characterization of a novel GJB1 variant (c.554C > T, p.Thr185Ile) in a CMTX1-affected family and its pathogenic impact using patient-derived induced pluripotent stem cells (iPSCs) and three-dimensional (3D) neural organoid models. The GJB1 gene encodes connexin 32 (Cx32), a gap junction protein. Immunofluorescent analysis revealed aberrant intracellular reduction and aggregation of the mutant Cx32 protein, suggesting impaired gap junction function. iPSC-derived neural organoids carrying the GJB1 mutation exhibited significant delay in neural differentiation and disrupted neural rosette organization. These findings underscore the critical role of Cx32 in neural development and provide a physiologically relevant platform for underlying CMTX1 pathological mechanisms on central nervous system. The established GJB1-variant organoid model holds promise for investigating genotype-phenotype correlations and facilitating the development of targeted therapeutic strategies for CMTX1.

Keywords:  Charcot-Marie-Tooth disease (CMT); Disease modeling; GJB1 variant; Neural organoids; X-linked neuropathy

DOI:  https://doi.org/10.1016/j.nbd.2026.107299