bims-axbals 2026-01-25 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–01–25
twenty-six papers selected by
TJ Krzystek

Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1, enhances autophagy which mitigates TDP-43 toxicity.
ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies.
Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.
Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.
Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies.
Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway.
GFP-free live neuron quantitative imaging reveals compartmentalization and growth dynamics of polyQ aggregates.
CK1δ-dependent SNAPIN dysregulation drives lysosomal failure in HIV-1 Vpr-exposed neurons: A targetable mechanism in HAND.
VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients.
Loss and gain of motor protein function cause microtubule bundle damage in Drosophila axons.
ER membrane receptors engage core autophagy machinery to initiate ER-phagy.
Rapid, Growth Factor-Reduced Differentiation of Functional Neurons from hiPSCs.
Mislocalization of FTD3-associated mutant CHMP2B to the nucleus of human neurons due to loss of a nuclear export signal.
Computational Exploration of the Molecular Mechanism of Epigallocatechin Gallate against TDP-43 Aggregation.
Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce the spread of pathology.
C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
The Role of Autophagy in Maintaining Human Health and Disease Prevention.
Multi-organoid loop cerebral connectoids exhibit enhanced neuronal network dynamics and sequence-specific entrainment.
Live cell imaging of exogenous α-synuclein fibrils in primary microglia and neuron co-cultures.
V-ATPase a3 Directs Secretory Lysosome Transport in Enamel Formation.
Dysregulation of store-operated calcium entry in fibroblast lines from adult and juvenile-onset Huntington's disease patients.
From TDP-43/RNA complex formation to disease-linked TDP-43 aggregation through a structural and cellular approach.
Linker extension impairs ESCRT-III flat spirals and the mediated membrane abscission.
The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting NaV1.7 and NaV1.8 nociceptive sodium channels.
DACIT device for axon cancer cell interaction testing in 2D and 3D.
Mitochondrial dysfunction and Ca2+ dysregulation in human iPSC-derived neurons carrying presenilin-1 mutation arise under stress via an MCU-1-independent mechanism.

Genetics. 2026 Jan 19. pii: iyag014. [Epub ahead of print]

Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1, enhances autophagy which mitigates TDP-43 toxicity.

Sei-Kyoung Park, Sangeun Park, Susan W Liebman.

  Cytoplasmic aggregation of nuclear proteins such as TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) is associated with several neurodegenerative diseases. Studies in higher cells suggest that aggregates of TDP-43 and FUS sequester polysomes by binding RACK1 (receptor for activated C kinase 1), a ribosomal protein, thereby inhibiting global translation and contributing to toxicity. However, RACK1 is also a scaffold protein with a role in many other cellular processes including autophagy. Using yeast, we find that deletion of the RACK1 ortholog, ribosomal protein ASC1, reduces TDP-43 toxicity, but not FUS toxicity. TDP-43 foci remain liquid like in the absence of ASC1 but they become smaller. This is consistent with findings in mammalian cells. However, using double label fluorescent tags and co-immunoprecipitation we establish that ASC1 does not co-localize with TDP-43 foci, challenging the polysome sequestration hypothesis. Instead, ASC1 appears to influence toxicity through regulation of autophagy. We previously showed that TDP-43 expression inhibits autophagy and TOROID (TORC1 Organized in Inhibited Domains) formation and that genetic modifiers that rescue yeast from TDP-43 toxicity reverse these effects. Here we show that FUS does not inhibit autophagy. Deletion of ASC1 enhances a non-canonical form of autophagy that effectively counteracts TDP-43 induced autophagy inhibition despite reduced TOROID formation. Our findings highlight autophagy-not polysome sequestration-as a key mechanism underlying ASC1-mediated modulation of TDP-43 toxicity and suggest autophagy as a promising therapeutic target.

Keywords:  ASC1/RACK1; FUS (fused in sarcoma); TDP-43 (TAR DNA-binding protein 43); TOROID; autophagy

DOI:  https://doi.org/10.1093/genetics/iyag014
Curr Opin Neurobiol. 2026 Jan 21. pii: S0959-4388(25)00194-1. [Epub ahead of print]97 103163

ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies.

Emmanuelle C Genin, Véronique Paquis-Flucklinger.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often overlaps clinically and pathologically with frontotemporal dementia (FTD), the second most common form of dementia. Like many neurodegenerative disorders, both ALS and FTD share a crucial pathological hallmark, the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. This process is referred to as proteinopathy. This review focuses on the proteinopathies associated with ALS, including aggregates of TDP-43, SOD1, FUS, and CHCHD10, which disrupt critical cellular processes such as RNA metabolism, mitochondrial function, and protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10-related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating ALS, as they directly target fundamental pathogenic mechanisms.

DOI: https://doi.org/10.1016/j.conb.2025.103163
Front Mol Neurosci. 2025 ;18 1686230

Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.

Saddam Muhammad Ishaq, Aaron P Russell.

  Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.

Keywords:  TDP-43; amyotrophic lateral sclerosis; brain; myogranule; skeletal muscle; spinal cord; stress granules

DOI:  https://doi.org/10.3389/fnmol.2025.1686230
Neurotherapeutics. 2026 Jan 17. pii: S1878-7479(26)00004-8. [Epub ahead of print] e00834

Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.

Marc Shenouda, Sandra Shenouda, Bryan Kartono, Shehab Eid, Cheryl Cheng, Janice Robertson.

  Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.

Keywords:  ALS; Chaperone; FTD; KPNB1; TDP-43; Therapeutic

DOI:  https://doi.org/10.1016/j.neurot.2026.e00834
bioRxiv. 2025 Dec 03. pii: 2025.12.01.691001. [Epub ahead of print]

Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies.

Trent A Gomberg, Sara Elmsaouri, Hema M Kopalle, Michael W Baughn, Melinda S Beccari, Melissa McAlonis-Downes, Jonathan W Artates, Deepak Pant, Harriet Mak, Aaron A Smargon, Tynan C Sander, Esaul Garcia, Dominic P Lee, Don W Cleveland, Gene W Yeo.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by the selective deterioration of motor neurons in the central nervous system (CNS). A key driver of this pathogenesis is nuclear loss of ALS-associated protein TDP-43, leading to mis-splicing of TDP-43 targets including important neuronal genes STMN2 and UNC13A . Here, we have developed a gene therapy strategy for ALS and related TDP-43 proteinopathies, to correct mis-splicing of both STMN2 and UNC13A cryptic exons using small nuclear RNAs (snRNAs) encoded from a single vector. We identified promoter sequence elements to increase therapeutic snRNA expression by 10-fold, then further optimized the expression cassette with combinatorial snRNA targeting to rescue multiple cryptic splicing targets. The engineered snRNAs restored normal pre-mRNA processing of both STMN2 and UNC13A transcripts despite TDP-43 loss of function, rescuing stathmin-2 protein levels in iPSC derived motor neurons, restoring their axonal regeneration capacity to wild-type levels. In addition, adeno-associated virus (AAV) delivery of the snRNAs to the murine central nervous system in the constitutive cryptic splicing model Stmn2 HumΔGU fully restored cortical Stmn2 pre-mRNA processing, highlighting the utility of snRNAs as a therapeutic modality in vivo . Together, this study demonstrates that snRNAs are a promising and versatile therapeutic strategy for the simultaneous correction of multiple aberrant transcripts affected by cryptic splicing in TDP-43 proteinopathies.

DOI: https://doi.org/10.64898/2025.12.01.691001
Expert Rev Neurother. 2026 Jan 21.

Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway.

Richard S Finkel, Thomas O Crawford, Basil T Darras, Thomas Brown, Mouhamed Gueye, Mary Schroth, Jena M Krueger, Laurent Servais.

   INTRODUCTION: In spinal muscular atrophy (SMA), irreversible loss of spinal motor neurons and progressive skeletal muscle atrophy cause continuous weakness and loss of motor function. Treatments that increase levels of survival motor neuron (SMN) protein in motor neurons have greatly improved prognoses for patients, but significant unmet needs remain. Myostatin is a protein secreted by skeletal muscle that acts as a negative regulator of muscle growth. Inhibition of the myostatin signaling pathway may improve motor function in SMA and other neuromuscular diseases.
AREAS COVERED: This article reviews the role of muscle in SMA and the potential for treatments that inhibit the myostatin signaling pathway in neuromuscular diseases. Preclinical and clinical trial data are discussed for these muscle-targeted treatments in development for SMA.
EXPERT OPINION: SMN-targeted disease-modifying treatments focus on motor neuron survival rather than muscle. Treated individuals nonetheless experience a range of persistent muscle weakness. Treatments that inhibit myostatin signaling represent a potential complementary pathway for direct muscle enhancement. In the evolving SMA treatment landscape, understanding how muscle-targeted treatment can be incorporated into clinical practice will facilitate individualized treatment decisions and identify outcomes that best encapsulate maintenance or improvement of motor function across the phenotypic spectrum of SMA.

Keywords:  Apitegromab; clinical trial; emugrobart; motor function; muscle atrophy; myostatin; neuromuscular; spinal muscular atrophy; taldefgrobep alfa

DOI:  https://doi.org/10.1080/14737175.2026.2621405
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2505321123

GFP-free live neuron quantitative imaging reveals compartmentalization and growth dynamics of polyQ aggregates.

Xiaotian Bi, Berea Suen, Li-En Lin, Kun Miao, Lu Wei.

  Huntington's Disease (HD), the most prevalent polyglutamine (polyQ) neurodegenerative disorder, features brain aggregates induced by mutant huntingtin (mHtt) proteins harboring expanded polyQ tracts. Despite extensive efforts, molecular mechanisms of polyQ aggregates remain elusive. Here, we establish quantitative stimulated Raman scattering imaging of polyQ aggregates (q-aggSRS) for noninvasive investigations in live neuronal cocultures using deuterated glutamine labeling. Q-aggSRS allows for specific visualization by targeting the distinct Raman peak from carbon-deuterium bonds, eliminating the need for bulky fluorescent protein tagging (e.g., EGFP). Coupled with analysis from aggregate-tailored expansion microscopy, newly designed two-color imaging, and pulse-chase visualization, we comprehensively quantified the mHtt and non-mHtt proteins within the same aggregates across varying sizes, cell types, mHtt constructs, and subcellular locations. Our findings demonstrate a two-phase aggregate model with a distinct core-shell spatial organization, reveal significant heterogeneity in nucleus/cytoplasm compartmentalization specific to neurons, and identify previously unrecognized loosely packed aggregates specifically in neuronal nuclei. These insights should advance our understanding of native polyQ aggregates, and our proposed interaction coefficients may offer quantitative parameters for developing effective HD therapies.

Keywords:  live-neuronal imaging; protein aggregation; stimulated Raman scattering microscopy

DOI:  https://doi.org/10.1073/pnas.2505321123
iScience. 2026 Feb 20. 29(2): 114544

CK1δ-dependent SNAPIN dysregulation drives lysosomal failure in HIV-1 Vpr-exposed neurons: A targetable mechanism in HAND.

Bassel E Sawaya, Maryline Santerre.

  HIV-associated neurocognitive disorders (HANDs) persist in nearly 40% of virally suppressed individuals despite antiretroviral therapy (ART). Lysosomal dysfunction has emerged as a key contributor to HAND pathogenesis, yet the molecular mechanisms linking chronic HIV exposure to impaired neuronal degradation remain incompletely defined. Here, we identify HIV-1 viral protein R (Vpr) as a driver of lysosomal acidification failure, clustering, and degradative impairment in neurons. We report casein kinase 1 delta (CK1δ) as a central mediator of this dysfunction, acting via phosphorylation of the adapter protein SNAPIN. Vpr-induced CK1δ activation leads to hyperphosphorylation of SNAPIN, disrupting lysosomal positioning and motility. These defects are rescued by selective CK1δ inhibition, which restores lysosomal acidification, positioning, and mitophagy. Our findings define a Vpr-CK1δ-SNAPIN axis that contributes to HANDs and highlight lysosomal transport as a targetable mechanism in neurodegeneration.

Keywords:  Biochemistry; Pharmacology; Virology

DOI:  https://doi.org/10.1016/j.isci.2025.114544
Mov Disord. 2026 Jan 19.

VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients.

Dajana Grossmann, Adrian Spranger, Emily Fischer, Johanna W Schubarth, Jenny Leopold, Hannes Glaß, Sebastian Klicker, My Uyen Dang Thi, Anna Elisabeth Bartalis, Andreas Hermann, Kevin Peikert.

   BACKGROUND: Membrane contact sites are crucial for the exchange of ions or lipids and thus are critical for the function and maintenance of organelles. VPS13A is a membrane-residing, bridge-like protein connecting two membranes to enable bulk lipid transfer. Loss-of-function mutations in the VPS13A gene cause VPS13A disease. Previous studies showed alterations of lipid transfer and impaired calcium homeostasis.
OBJECTIVE: Although membrane contact sites are becoming increasingly important in neurodegenerative disease research, their contribution to cellular homeostasis is still unclear. We attempted to investigate the consequences of loss of VPS13A function on membrane contact sites and related mechanisms in the context of VPS13A disease.
METHODS: VPS13A-deficient patient-derived fibroblasts were compared with fibroblasts from healthy donors. Specific dyes, labeled fatty acids, and a specific marker for mitochondrial-endoplasmic reticulum contact sites were used to investigate lipid transfer and distribution in involved organelles. Mitochondrial calcium handling was investigated using the calcium indicator Rhod-2, AM. Images were obtained by super-resolution microscopy using Airyscan2 technology.
RESULTS: We observed a general disturbance of membrane contact sites in VPS13A disease, accompanied by a reduction in lipid droplet formation, diminished lipid transfer into mitochondria, and unusual mitochondrial calcium uptake behavior in VPS13A disease fibroblasts.
CONCLUSIONS: Loss of VPS13A causes alterations beyond an impairment of lipid shuttling, which includes a dysregulation of membrane contact sites as well as impaired mitochondrial calcium handling. Accordingly, our findings contribute significantly to the understanding of mechanisms directly or indirectly linked to the function of VPS13A. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  Bridge‐like lipid‐transport proteins (BLTPs); MERCS; VPS13A; calcium; lipids; mitochondria

DOI:  https://doi.org/10.1002/mds.70177
Curr Biol. 2026 Jan 19. pii: S0960-9822(25)01691-4. [Epub ahead of print]

Loss and gain of motor protein function cause microtubule bundle damage in Drosophila axons.

Yu-Ting Liew, Milli Owens, David M D Bailey, William Cairns, Maureece Day, Ella Jones, Sophie McCann, Lydia Lorenzo-Cisneros, Thomas Murphy, Jill Parkin, Haydn Tortoishell, Federico Dajas-Bailador, Matthias Landgraf, Devesh C Pant, André Voelzmann, Andreas Prokop.

  Neurodegeneration often starts by atrophy of the cable-like nerve fibers (axons) that wire nervous systems. Maintaining axons requires supply via motor-protein-driven transport along uninterrupted bundles of microtubules. Functional loss of motor proteins, but surprisingly also their hyperactivation, links to conditions of axonal atrophy; in both cases the underlying mechanisms are little understood. To bridge this important knowledge gap, we carried out systematic studies using 40 different genetic tools to manipulate 19 context-related genes in one standardized Drosophila primary neuron system. Starting with transport motors, we found that downregulation in at least three of them-dynein heavy chain, the kinesin family member 5 (KIF5) ortholog kinesin heavy chain (Khc), and KIF1A ortholog Unc-104-caused disintegration of axonal microtubule bundles, which we refer to as "microtubule-curling"; this damages the essential highways for life-sustaining axonal transport. To understand this phenomenon, we focused on Khc's various subfunctions. We found that abolishing Khc-mediated mitochondrial and lysosomal transport affects the homeostasis of reactive oxygen species (ROS), which in turn triggers microtubule-curling in fly and mouse neurons alike. Taking the opposite approach by using conditions where Khc is hyperactive, we observed comparable microtubule-curling, triggered by an ROS-independent mechanism likely involving excessive mechanical force generation. To assess wider relevance of our findings, we studied Unc-104, its binding partner KIF-binding protein (KIFBP), and human KIF5A. These studies suggest that functional loss and hyperactivation of other transport motors also cause ROS-dependent and -independent microtubule-curling, which could therefore represent two fundamental pathways that link transport motors to microtubule bundle decay and neurodegeneration.

Keywords:  Drosophila; ROS; axonal transport; axons; dynein; kinesin; microtubules; mitochondria; neurodegeneration; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cub.2025.12.038
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2523465123

ER membrane receptors engage core autophagy machinery to initiate ER-phagy.

Cha Wu, Haixia Yang, Chen Wang, Peiqi Huang, Ning Yan, Ruobing Ren, Wei Liu, Yi Lu, Chunmei Chang.

  Endoplasmic reticulum (ER) phagy is the form of selective autophagy that governs ER abundance and integrity by targeting dysfunctional ER fragments for degradation. How the recognition of ER fragments as autophagy substrates is coupled to engagement of the core autophagic machinery is largely unknown. Here, using a combination of in vitro reconstitution systems, structural modeling, and cell biology, we demonstrate that ER membrane receptors directly engage the core autophagy component ATG9A, as well as the PI3P-binding protein WIPI2, to initiate ER-associated autophagosome biogenesis. ER-phagy receptor-ATG9A association nucleates the recruitment of the other key autophagy proteins required to initiate ER-phagy. In parallel, ER-phagy receptor-WIPI2 engagement promotes rapid LC3 lipidation for autophagic membrane expansion. These data show how ER-phagy receptors trigger the cascade of events leading to ER autophagosome formation.

Keywords:  ER-phagy; ER-phagy receptor; autophagosome biogenesis; autophagy machinery; in vitro reconstitution

DOI:  https://doi.org/10.1073/pnas.2523465123
bioRxiv. 2025 Dec 03. pii: 2025.12.03.692194. [Epub ahead of print]

Rapid, Growth Factor-Reduced Differentiation of Functional Neurons from hiPSCs.

Natalie A Parker, Oluwadamilola E Kolawole, Zhixin Liao, Farsin S Syed, Kara E Moquin, Nisha R Iyer.

Introduction: Human induced pluripotent stem cells (hiPSCs) can be rapidly converted into neurons via NGN2 overexpression, but many protocols require costly reagents during the initial induction phase that may limit adoption by labs without routine neuronal differenitation experience. We developed a simplified, low-cost protocol using a tetracyline-inducible (TET-on) NGN2 system in minimal media to generate cortical neurons in as little as 6 days.
Methods: KOLF2.1J hiPSCs were stably transfected with a TET-on NGN2 cassette using the nonviral PiggyBac system and induced with doxycycline in Essential 6 media. The impact of adding the Notch inhibitor, DAPT, during doxycycline induction to enhance neurogenesis to was evaluated with immunocytochemistry (ICC) and RT-PCR. Following induction neurons were matured and characterized with ICC for mature neuronal markers and by multielectrode array recordings for functional network activity.
Results: DAPT markedly improved conversion efficiency, reducing non-neuronal cells and increasing pan-neuronal TUJ1 expression. Resulting neurons expressed cortical markers and matured into functional glutamatergic neurons. MEA recordings showed spontaneous activity by day 14 and synchronous network firing by day 35. Secondary PB transfection enabled Td-Tomato labelling of KOLF2.1J:pB-TO-NGN2 hiPSCs, allowing 24-hour live imaging of neurite outgrowth.
Conclusion: This streamlined, growth-factor-free workflow provides an accessible route for generating functional neurons from patient-derived hiPSCs, including in labs with limited hiPSC or neuronal culture experience.

DOI: https://doi.org/10.64898/2025.12.03.692194
Acta Neuropathol Commun. 2026 Jan 20.

Mislocalization of FTD3-associated mutant CHMP2B to the nucleus of human neurons due to loss of a nuclear export signal.

Yong-Woo Jun, Evan P Hass, Soojin Lee, Thomas G Fazzio, Fen-Biao Gao.

  Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2BIn5 and CHMP2BΔ10. Here, we found that wildtype CHMP2B (CHMP2BWT) is mostly present in the cytoplasm, but CHMP2BIn5 is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2BWT and ALS-associated CHMP2BQ206H, and its loss in CHMP2BIn5 is responsible for the observed nuclear mislocalization. CHMP2BΔ10 remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2BIn5 in FTD3 pathogenesis.

Keywords:  CHMP2B; CRM1; Cytoplasm; ESCRT; Export; FTD; Neurons; Nuclear export signal; Nucleus; iPSC

DOI:  https://doi.org/10.1186/s40478-026-02222-0
J Chem Inf Model. 2026 Jan 20.

Computational Exploration of the Molecular Mechanism of Epigallocatechin Gallate against TDP-43 Aggregation.

Wenjuan Yi, Zhengdong Xu, Dushuo Feng, Lulu Guan, Jiaxing Tang, Yu Zou.

Cytoplasmic accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates represents the primary pathological hallmark of TDP-43 proteinopathies including amyotrophic lateral sclerosis (ALS) and chronic traumatic encephalopathy (CTE). Inhibiting TDP-43 aggregation or disrupting its preformed fibrils might be promising strategies to prevent or delay the development of TDP-43 proteinopathies. Recently, the green tea polyphenol, epigallocatechin gallate (EGCG), was observed to prevent the formation of TDP-43 oligomeric species and fibrillar aggregates. Nevertheless, the atomic-level mechanism of this inhibition has been incompletely characterized. In this study, we performed a multitude of replica exchange with solute tempering 2 (REST2) and all-atom molecular dynamics (MD) simulations of 46.8 μs in total on TDP-43 models with and without EGCG. The REST2 simulation results revealed that EGCG impedes the β-sheet structure formation and interferes the interchain interaction of TDP-43304-348 dimer. Subsequent analyses show that EGCG could alter the distribution of free energy landscape and hinder the residue-residue interaction of the dimer. The binding analyses confirmed that EGCG preferentially bound to M307, F313, F316, W334, M339, Q344, and Q346 residues, and hydrophobic, polar, and π-π stacking interactions dominate the binding of EGCG on the dimer. Additional conventional molecular dynamics (MD) simulations demonstrated that the protofibrillar tetramer is the minimal stable TDP-43304-348 protofibril. Taking the tetramer as a protofibril model, we found that EGCG could reduce the structural stability and disrupt the β-sheet structure of TDP-43304-348 protofibril, thus possessing a destabilization effect on its higher-order structure. This investigation unveils the atomic-level mechanism by which EGCG against TDP-43 aggregation, which may provide potential fundamental knowledge of therapeutic strategies for TDP-43 proteinopathies.

DOI: https://doi.org/10.1021/acs.jcim.5c02616
Neurobiol Dis. 2026 Jan 18. pii: S0969-9961(26)00021-5. [Epub ahead of print] 107277

Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce the spread of pathology.

Lindsay M Roth, Olga Morozova, Jan Stöhr, Jason Schapansky.

  Parkinson's Disease (PD) is a neurodegenerative disorder that results from a loss of dopaminergic neurons in the substantia nigra. A pathological hallmark of PD is proteinaceous inclusions called Lewy body aggregates, which consist primarily of misfolded neuronal alpha-synuclein (αSyn). PD pathology progression is thought to be driven by a prion-like spread of αSyn aggregates between adjacent neurons; however, the role of other cell types, such as pathology bearing astrocytes, in this process is still elusive. αSyn pathology has been observed in PD patient astrocytes, suggesting that astrocytes could be involved in the processing of aggregates. Therefore, we examined the interaction of astrocytes with αSyn pre-formed fibrils (PFFs) and explored how these cells might modulate the spread of seed-competent αSyn in astrocyte-neuron co-cultures. Isolated primary astrocytes rapidly internalized and degraded αSyn PFFs within hours of internalization. Upon exposure to lysosome compromising agents, such as chloroquine or cathepsin B inhibitors leupeptin or CA-074, degradation of αSyn PFFs was significantly reduced. The addition of astrocytes to primary neuron cultures reduced endogenous αSyn aggregation caused by exogenous αSyn PFFs, indicating that astrocytes may mitigate αSyn pathology in the brain. The addition of lysosome-compromised (LC) astrocytes to primary neuron cultures limited this anti-seeding effect. Finally, LC astrocytes, preloaded with PFFs and added to neuronal cultures, induced αSyn pathology in neurons, whereas unimpaired, PFF-preloaded astrocytes did not. These data suggest that astrocytes can modulate and contribute to the spread of αSyn pathology, significantly contributing to PD pathogenesis.

Keywords:  Alpha-synuclein; Astrocytes; Co-culture; Lysosomes; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nbd.2026.107277
Autophagy. 2026 Jan 22.

C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.

Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.

  Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.

Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2621110
Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2026 Jan 23. 42 e20260004

The Role of Autophagy in Maintaining Human Health and Disease Prevention.

Harsha Icharam Narkhede, Karan Jayantilal Jain, Ishita Sanjay Dalvi, Umesh Bhagaji Gite.

  Autophagy, a highly conserved catabolic process, plays a fundamental role in maintaining cellular homeostasis by degrading and recycling unnecessary or dysfunctional cellular components through lysosomal pathways. It serves as a vital mechanism for clearing damaged proteins, organelles, and other cytoplasmic constituents, ensuring the cell's functional integrity, especially under stress conditions such as nutrient deprivation. Various forms of autophagy macro-autophagy, micro-autophagy, and chaperone-mediated autophagy are involved in distinct regulatory pathways that respond to different physiological and pathological stimuli. Recent research continues to uncover the molecular underpinnings and biological significance of these pathways, emphasizing their critical contributions to human health and disease.

Keywords:  Autophagosome; Lysosome; Phagophore; Protein Degradation; mTOR Pathway

DOI:  https://doi.org/10.62958/j.cjap.2026.004
Commun Biol. 2026 Jan 22.

Multi-organoid loop cerebral connectoids exhibit enhanced neuronal network dynamics and sequence-specific entrainment.

Tomoya Duenki, Yoshiho Ikeuchi.

Reconstructing networks of neurons in vitro is essential for advancing our understanding of functional mechanisms and disease pathogenesis. However, neuronal culture methods including organoids are limited in network structure complexity required for their functionality and dynamics. In this study, we present modular organoid network tissues - loop connectoids - in which multiple cerebral organoids are connected via axon bundles using microfluidic devices. We compared network activity of three- and four-membered loop cerebral connectoids, two reciprocally connected organoids, and single organoids. We observed a significant trend in larger organoid networks exhibiting more complex activity, showing longer activity periods, more bursts, and richer temporal patterns. Additionally, the activity in connectoids shifts closer to a critical state, a hallmark of efficient information processing in the brain, as more organoids are connected. Pharmacological perturbation reveals prominent excitatory and inhibitory responses, supporting the physiological relevance of the observed dynamics. Furthermore, optogenetic stimulation of organoids in a specific sequence can influence their spontaneous activity propagation pattern within the network. This work represents a foundational step toward constructing more complex and physiologically relevant neural networks in vitro, offering a platform for studying neuronal network function and therapeutic intervention.

DOI: https://doi.org/10.1038/s42003-026-09589-9
Biochem Biophys Rep. 2026 Mar;45 102416

Live cell imaging of exogenous α-synuclein fibrils in primary microglia and neuron co-cultures.

C Paquette, T Charlton, N Prowse, T Fortin, H Sun, S Hayley.

  α-synuclein (α-syn) rich Lewy bodies are a prominent pathological feature of Parkinson's disease (PD), with intra-cellular accumulation occurring in neurons and possibly microglia. Tracking α-syn movement between the two different cell types is of critical importance in determining how pathology spreads. We hypothesized that the separate pre-treatment of either primary cortical neurons or microglia with exogenous α-syn preformed fibrils (PFFs) will foster a cytotoxic environment when co-cultured with the opposite naïve cell type. To this end, using real time live cell imaging, we found an accumulation of Alexa Fluor 488 labelled α-syn PFFs in both microglia and neurons. In the co-cultures, the labelled-PFFs showed differing patterns of spread to non-seeded cells. The PFF treatment also provoked cellular loss that increased with the passage of time and induced marked vacuolation and changes in microglial morphology. Microglia appeared to accumulate PFFs from morphologically compromised neurons and shifted to a predominately dystrophic and "foamy enlarged fried egg" morphology over time and was associated with a reduction in levels of the anti-inflammatory cytokine, interleukin-4 (IL-4). We currently provide a novel in vitro co-culture model that allows for tracking α-syn spread between primary cortical microglia and neurons.

Keywords:  A-synuclein; Co-culture; Cytokine; Inflammatory; Microglia; Parkinson's

DOI:  https://doi.org/10.1016/j.bbrep.2025.102416
J Dent Res. 2026 Jan 21. 220345251401512

V-ATPase a3 Directs Secretory Lysosome Transport in Enamel Formation.

K Otsu, S Ikezaki, N Goto-Matsumoto, A Ikarashi, H Sano, H Ida-Yonemochi, H Ohshima, G-H Sun-Wada, Y Wada, M Nakanishi-Matsui, H Harada.

  Enamel mineralization critically depends on maturation-stage ameloblasts (M-ABs) regulating pH, protein secretion, and cell-matrix adhesion. However, the molecular mechanisms underlying these processes remain poorly understood. This study identifies the vacuolar-type H+-ATPase (V-ATPase) a3 subunit as a key regulator of enamel formation via its role in secretory lysosome trafficking. In a3 knockout (a3KO) mice and cultured ameloblasts, a3 is required for both lysosomal acidification and the directional transport of odontogenic ameloblast-associated protein (ODAM)-containing secretory lysosomes to the ruffled border membrane of M-ABs. At this site, ODAM is crucial for mediating ameloblast adhesion to the enamel matrix. Loss of a3 caused severe enamel hypomineralization, characterized by reduced matrix acidification, cystic enamel defects, abnormal ruffled border morphology, and ameloblast detachment from the mineralizing surface. In vitro, a3-deficient ameloblasts exhibited significantly impaired adhesion to hydroxyapatite, decreased ODAM expression, and suppressed lysosomal acidification, indicating a3 is functionally required for maintaining ameloblast function and polarity. Mechanistically, Rab27A served as an important adaptor linking a3-positive secretory lysosomes to the microtubule network, enabling their polarized movement toward the distal plasma membrane. Disruption of this a3-Rab27A axis in a3KO cells mislocalized secretory lysosomes and defective ODAM delivery into the enamel matrix, compromising enamel mineralization. These findings reveal a new mechanism by which a3 orchestrates lysosomal positioning and ODAM secretion in enamel-forming cells. By integrating proton transport with vesicular trafficking and adhesion protein delivery, a3 functions as a key regulator of enamel mineralization. This study provides new insights into the pathogenesis of enamel hypomineralization and identifies a3 and its associated pathways as potential therapeutic targets for treating developmental enamel defects.

Keywords:  a3 knockout mice; enamel mineralization; hypomineralization; maturation-stage ameloblasts; odontogenic ameloblast-associated protein; vacuolar-type H+-ATPase

DOI:  https://doi.org/10.1177/00220345251401512
Pharmacol Rep. 2026 Jan 20.

Dysregulation of store-operated calcium entry in fibroblast lines from adult and juvenile-onset Huntington's disease patients.

Samuel Oluwafemi Egbuwalo, Ewelina Latoszek, Hana Hansíková, Jiří Klempíř, Alžbeta Mühlbäck, Georg Bernhard Landwehrmeyer, Jacek Kuźnicki, Magdalena Czeredys.

   BACKGROUND: The pathology of Huntington's disease (HD) is marked by the aggregation of mutant huntingtin protein (mHTT), which results from expanded polyglutamine (polyQ) residues encoded by CAG repeats in the HTT gene. These repeats are differentially elongated in adult- and juvenile-onset HD. In striatal neurons, the mHTT disrupts cellular mechanisms such as store-operated calcium entry (SOCE), a process in which endoplasmic reticulum Ca²⁺ depletion triggers extracellular Ca²⁺ influx; however, this process can also be affected in peripheral cells. The aim of this study was to evaluate SOCE in fibroblasts derived from both HD onset patients and age-related controls.
METHODS: We conducted SOCE analysis in dermal fibroblasts from 12 HD patients (including adult- and juvenile-onset subtypes) and age-related healthy controls using Fura-2 AM ratiometric imaging paired with EGTA-based extracellular calcium chelation protocols. To evaluate SOCE response, we administered two SOC channel inhibitors, 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1-amine hydrochloride (C20H22BrClN2) and EVP4593, in premanifest HD fibroblasts.
RESULTS: In healthy human fibroblast lines, a decline in SOCE was observed between juvenile and adult individuals. In fibroblast lines from adult-onset HD patients (premanifest, early manifest, and manifest stages), we observed increased SOC channel activity. Conversely, juvenile-onset HD fibroblast lines exhibited reduced SOC channel activity compared to controls. Notably, SOCE dysregulation was independent of CAG repeat length in HD lines. Both SOC channel inhibitors attenuated SOCE in adult-onset HD lines.
CONCLUSION: The mHTT upregulates SOCE in adult-onset HD fibroblasts and downregulates it in juvenile-onset HD fibroblast lines; however, SOCE levels do not correlate with the length of CAG repeats encoding mHTT. Despite opposing trends compared to age-related controls, similar levels of SOCE in both HD-onset fibroblasts were detected. Both C20H22BrClN2 and EVP4593 show potential for stabilizing SOCE in adult-onset HD. These findings suggest that dysregulated SOCE could be investigated as a peripheral target for studying pathological processes potentially associated with Huntington's disease.

Keywords:  Fibroblasts; Huntingtin; Huntington’s disease; SOCE

DOI:  https://doi.org/10.1007/s43440-025-00820-8
Nat Commun. 2026 Jan 21.

From TDP-43/RNA complex formation to disease-linked TDP-43 aggregation through a structural and cellular approach.

Yitian Feng, Vandana Joshi, Serhii Pankivskyi, Marie-Jeanne Clément, Juan Carlos Rengifo-Gonzalez, Aurélien Thureau, David Pastré, Ahmed Bouhss.

Many RNA-binding proteins (RBP) have been associated to several neurodegenerative diseases for which RBP-rich cytoplasmic inclusions represent a major histological hallmark. However, among RBPs, the occurrence with which TDP-43, a nuclear mRNA-binding protein, is detected in cytoplasmic inclusions is exceptionally high. To unravel the underlying mechanisms, we focus our analysis on the structured N-terminal domain (NTD) of TDP-43, which is distinct among RBPs as this domain mostly initiates TDP-43 homotypic interactions. Through an in depth structural analysis, we successively show that the cooperative binding of TDP-43 along long GU-rich intronic sequences antagonizes NTD/NTD interactions between adjacent TDP-43 along mRNA. In contrast, the TDP-43 cooperativity facilitates NTD/NTD interactions between TDP-43 located on distinct GU-rich sequences. We hypothesize that NTD/NTD interactions between distinct GU-rich sequences efficiently allow the compaction of long introns in neurons under physiological conditions. However, when the binding of TDP-43 to RNA is discontinuous because of a lack of cooperativity, aberrant NTD/NTD interactions between adjacent TDP-43 take place, promoting the aggregation of TDP-43 RRMs (RNA Recognition Motifs) under stress conditions. Altogether, we provide a detailed view of the physiological assembly of TDP-43 on introns and the putative weaknesses of TDP-43 that makes it distinct in its propensity for aggregation compared to other RBPs.

DOI: https://doi.org/10.1038/s41467-026-68346-y
J Cell Biol. 2026 Apr 06. pii: e202503160. [Epub ahead of print]225(4):

Linker extension impairs ESCRT-III flat spirals and the mediated membrane abscission.

Mingdong Liu, Liuyan Yang, Rong Huang, Lei Qi, Tiefeng Song, Yuxuan Huang, Yunhui Liu, Yu-Zhong Zhang, Yong Wang, Qing-Tao Shen.

The endosomal sorting complex required for transport III (ESCRT-III) is conserved machinery that drives membrane abscission. While ESCRT-III flat spirals are proposed as a primed state, their essential role and regulation remain unclear. Leveraging our newly resolved architecture of yeast Snf7 flat spirals, we engineered a series of Snf7 mutants by inserting polyglycines into the linker between the helices α4 and α5. Our results demonstrate that extending the linker can transform Snf7 flat spirals into rings. Cryogenic electron microscopy analyses of these Snf7 rings reveal that the linker extension specifically relaxes α2/3 into a bent conformation while leaving other regions of Snf7 unaffected. Importantly, Snf7 rings are unable to mediate membrane abscission to form intraluminal vesicles, resulting in pronounced yeast sensitivity to extracellular canavanine. Our work identifies the linker as a critical regulator of ESCRT-III spiral assembly and establishes flat spirals as indispensable for membrane abscission, offering fundamental molecular insights into the membrane abscission mediated by ESCRT-III flat spirals.

DOI: https://doi.org/10.1083/jcb.202503160
Neuropsychopharmacology. 2026 Jan 21.

The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting NaV1.7 and NaV1.8 nociceptive sodium channels.

Yossef Maatuf, Ariel Iskimov, Alexander M Binshtok, Avi Priel.

Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC inhibits the excitability of nociceptive neurons. We show that THC directly targets the nociceptive voltage-gated sodium channels NaV1.7 and NaV1.8 through the conserved local anesthetic binding site. This interaction reduces sodium currents and suppresses action potential generation in peripheral sensory neurons. Our findings demonstrate that, beyond its central psychoactivity, THC exerts direct peripheral nociceptor inhibition via modulation of NaV1.7 and NaV1.8, offering new insight into cannabinoid-based analgesia independent of cannabinoid receptor signaling.

DOI: https://doi.org/10.1038/s41386-026-02355-9
iScience. 2026 Feb 20. 29(2): 114557

DACIT device for axon cancer cell interaction testing in 2D and 3D.

Ines Velazquez-Quesada, Vahid Alizadeh, Kara Allison, Elizaveta Belova, Svetllana Kallogjerovic, Natasha Hesketh, Xiaotian Zhang, Gareth Thomas, Erkan Tüzel, Bojana Gligorijevic.

  Peripheral innervation is increasingly recognized as a critical regulator of tumor progression, yet in vitro models that enable controlled study of axon-cancer cell interactions remain limited. Here, we present the Device for Axon-Cancer cell Interaction Testing in 2D and 3D (DACIT), a microfluidic platform that spatially separates neuronal somas from axons and cancer cells. This configuration supports experimental designs where compartments can be exposed to either identical or distinct conditions. Moreover, the channel height allows the incorporation and monitoring of tumor spheroids, enabling quantification of tumor growth and 3D invasion. We demonstrate DACIT compatibility with common cellular assays, including immunofluorescence, invadopodia assays, pharmacological perturbations, live-cell imaging, and 3D spheroid invasion. Together, these features establish DACIT as a versatile tool to interrogate how peripheral axons influence cancer cell behavior.

Keywords:  Biological sciences; Cancer; Cell biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.114557
Sci Rep. 2026 Jan 22.

Mitochondrial dysfunction and Ca2+ dysregulation in human iPSC-derived neurons carrying presenilin-1 mutation arise under stress via an MCU-1-independent mechanism.

Carlos Wilson, Pablo Galeano, María Mónica Remedi, Gisela Vanina Novack, Lorenzo Campanelli, Laura Gastaldi, Esteban Miglietta, Andres Hugo Rossi, Natividad Olivar, Luis Ignacio Brusco, Eduardo Miguel Castaño, Alfredo Cáceres, Laura Morelli.



Keywords:  Alzheimer; Calcium homeostasis; Cultured neurons; Mitochondrial dysfunction; iPSC

DOI:  https://doi.org/10.1038/s41598-026-35597-0