bims-axbals 2025-11-09 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2025–11–09
thirty-two papers selected by
TJ Krzystek

Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.
TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila.
The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
Aberrant NSUN1 activity connects m5C-RNA modification to TDP-43 neurotoxicity in ALS/FTD.
Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans.
Microfluidic Chip for Axonal Injury Models Construction and Enabling Multi-Omics Analysis.
The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.
Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.
Loss of Fanconi anemia proteins causes a reliance on lysosomal exocytosis.
Glutamic Acid at Position 168 Is a Constitutive Activator of Tank Binding Kinase 1 Catalytic Function.
Herkinorin Promotes μ-Opioid Receptor Internalization and Protects iPSC-Derived Neurons from Hypoxic/Ischemic Injury.
Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons.
Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β.
Rethinking neurodegeneration through a co-proteinopathy lens.
Leveraging Proteomics to Explore the Molecular Mechanisms of Primary Tauopathies.
USH2A-Mutated Human Retinal Organoids Model Rod-Cone Dystrophy.
Unraveling the genetic landscape of ALS in Greece: identification of known and novel causative variants in a 353-patient cohort.
The Role of DEAF1 in Dendritic and Synaptic Development: Insights Into Neurodevelopmental Disorders.
Delivering Progranulin to Astrocytic Lysosomes Promotes Growth of Co-Cultured Neurons.
An iPSC-derived model for drug screening in cerebral small vessel disease.
Cell Surface LAMP-2C Is Internalized in a Clathrin-Dependent Manner and Transported to the Recycling and Lysosomal Pathways.
Functional role for cas cytoplasmic adaptor proteins during cortical axon pathfinding.
A Hierarchical Cascade of Organellar Silencing and Their Regeneration Under Anaesthetic Stress in Plants.
Perspectives on the utilization of cell-free DNA in amyotrophic lateral sclerosis (ALS) diagnostics and prognostics - insight from cancer research.
Lysosomal and mTORC1 signaling dysregulation underpin the pathology of spastic paraplegia type 80.
A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders.
Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.
CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes.
Membrane curvature at the ER-PM contact sites.
FBXW7-mediated CHK2 regulation modulates DNA damage response and cellular stability in Huntington's disease.
Bni5 regulates and coordinates septin architecture and myosin-II functions at the cell division site.

Mol Med. 2025 Nov 05. 31(1): 328

Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.

Andrea Salzinger, Esra Özkan, Vidya Ramesh, Jyoti Nanda, Karen Burr, David Story, Nhan T Pham, Siddharthan Chandran, Bhuvaneish T Selvaraj.

   BACKGROUND: The neuromuscular junction (NMJ) is the synapse between motor neurons and skeletal muscle and controlls movement. Impaired synaptic transmission and NMJ degeneration has been observed during healthy ageing and is also implicated in several neuromuscular diseases. On account of the high energy demands of being distally located and large sized, NMJs are enriched with mitochondria. This enrichment is dependent on transport of mitochondria across the axon to the NMJ.
METHODS: We first established a human 3D neuromuscular assembloid model to study in-vitro NMJs, by fusing human stem cell derived spinal cord organoids and primary skeletal muscle organoids. To determine whether enhancing axonal mitochondrial transport modulates NMJ formation and maintenance, we generated a CRISPR-Cas9 meditated knock-out of syntaphilin in human stem cells.
RESULTS: Firstly, we characterised the neuromuscular assembloid model which showed functional innervated NMJs as measured by juxtaposed neurofilament+ axons and α-bungarotoxin+ acetylcholine receptors. Secondly, we showed that spinal cord selective genetic ablation of syntaphilin - an axonally localised mitochondrial anchor protein - resulted in increased mitochondrial motility in motor neurons, and consequently increased axonal density and NMJ formation.
CONCLUSION: This proof-of-concept study demonstrated that enhancing mitochondrial mobility could provide a therapeutic target to prevent NMJ degeneration.

Keywords:  Assembloid; Axonal transport; Mitochondria; Neuromuscular diseases; Neuromuscular junction; Organoid; Stem cells

DOI:  https://doi.org/10.1186/s10020-025-01319-x
Front Cell Dev Biol. 2025 ;13 1677090

TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila.

Davide Colaianni, Nadia Ceccato, Pietro Antolini, Carmela Conte, Cristiano De Pittà, Fabian Feiguin, Gabriella M Mazzotta.

  Transactive response DNA-binding protein 43 (TDP-43) is a key factor in motor neurons and related neurodegenerative disorders, and the presence of cytoplasmic aggregates of TDP-43 is a major hallmark of diseases such amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nevertheless, little is known about early developmental effects or the systemic nature of TDP-43-mediated pathology. Drosophila melanogaster is acknowledged as a powerful genetic model for studying the genetic inheritance and the behavioral and developmental processes associated with human neurodegenerative diseases, including ALS. To better understand the possible roles and potential pathogenic mechanisms of TDP-43 protein in the pathogenesis of ALS, we performed a transcriptomic analysis of larvae from a Drosophila model knock-out (KO) for the TBPH gene, the fly TDP-43 ortholog. Interestingly, the Gene Ontology (GO) analysis highlighted some pathways not yet associated with this pathology and this model. We identified several genes encoding for serine proteases, a class of enzymes that in the central nervous system (CNS) play important roles in neural development, synaptic plasticity, and neurodegeneration. Our work provides insights into novel pathological mechanisms underlying the disease, thereby opening new pathways for drug discovery.

Keywords:  Drosophila melanogaster; TBPH; TDP-43; amyotrophic lateral sclerosis; gene expression

DOI:  https://doi.org/10.3389/fcell.2025.1677090
Sci Rep. 2025 Nov 07. 15(1): 39117

The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.

Stefan Redl, Felix Von Zweydorf, Christian J Gloeckner, Inmaculada Posadas, Valentín Ceña, Michael W Hess, Giovanni Piccoli, María Dolores Pérez-Carrión.

  Parkinson's disease (PD) is a neurodegenerative pathology characterized by movement-associated symptoms due to the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Autophagy is an essential mechanism that restores homeostasis and promotes cell survival. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are among the most common in the familial cases. The LRRK2 E193K mutation falls in the Armadillo (ARM) domain and modifies LRRK2 interactome. The role of LRRK2 in autophagy has been widely explored, but the impact of E193K mutation on autophagy remains unknown. We found that the E193K variant increases autophagy in primary fibroblasts obtained from an E193K carrier. By cryo-based electron microscopy we observed that E193K fibroblasts present a higher amount of phagophores/autophagosomes. We showed that LRRK2 binds to the Dynein-1 complex, an essential regulator of retrograde transport of autophagosomes. Noteworthy, the E193K mutation jeopardizes this interaction and increases the cellular sensitivity to 1-methyl-4-phenylpyridinium (MPP+) toxin in fibroblasts as well as in a heterologous cell model. Our study reveals that the LRRK2 E193K variant influences the autophagic regulation and suggests that the dysregulation of the LRRK2-Dynein-1 complex causes autophagic defects and, eventually, cell death.

Keywords:  Autophagy; Dynein-1 complex; LRRK2 protein; Organelle morphometry; Parkinson´s disease; Ultrastructure

DOI:  https://doi.org/10.1038/s41598-025-26716-4
Life Sci Alliance. 2026 Jan;pii: e202503297. [Epub ahead of print]9(1):

Aberrant NSUN1 activity connects m5C-RNA modification to TDP-43 neurotoxicity in ALS/FTD.

Melissa Parra-Torres, Kumara Dissanayake, James A Gray, Alistair J Langlands, Ridvan Kucuk, Marek Gierlinski, Claire Troakes, Andrew King, Leeanne McGurk.

In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear RNA-binding protein TDP-43 mislocalises to the cytoplasm and forms insoluble aggregates, but the mechanisms controlling this remain unclear. We define a native TDP-43 interactome in human SH-SY5Y cells and identify proteins linked to the 5-methylcytosine (m5C) RNA modification as highly enriched. Using a Drosophila model of TDP-43 pathology, we show that aberrant activity of m5C-RNA methyltransferases Nsun1 drives TDP-43-induced m5C-RNA hypermethylation, whereas Nsun1 down-regulation alleviates TDP-43-induced degeneration, lifespan deficits, and cytoplasmic accumulation. In human cells, TDP-43 selectively interacts with NSUN1 isoform 3 independently of RNA. Furthermore, NSUN1 is nucleolar and TDP-43 is largely nucleoplasmic, yet they interact in both compartments, suggesting functional roles beyond their predominant localisations. In ALS/FTD postmortem frontal cortex, NSUN1 isoform 3 persists, whereas the shorter isoform is reduced, suggesting that a pool of NSUN1 capable of contributing to pathological TDP-43 interactions remains in disease. These findings suggest that TDP-43 neurotoxicity is coupled to NSUN1 activation and m5C-RNA methylation, revealing a potential therapeutic axis in ALS/FTD.

DOI: https://doi.org/10.26508/lsa.202503297
Neurobiol Dis. 2025 Nov 03. pii: S0969-9961(25)00391-2. [Epub ahead of print] 107174

Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.

Bavavarshini Tamilselvam, Gitika Thakur, Ruth Mathew, Eric Chai, Jose Lopez, Zhenyu Chen, Weihai Zhan, Craig Blackstone, Xue-Jun Li.

  Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurological diseases characterized by axonal degeneration of corticospinal motor neurons. SPG15, a common autosomal recessive form of HSP, is caused by mutations in the ZFYVE26 gene that encodes the spastizin protein. Spastizin partially localizes to mitochondria, suggesting a potential role in mitochondrial function. To investigate this possibility and explore treatments to mitigate neurodegeneration caused by spastizin deficiency, SPG15 patient-specific induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts and differentiated into cortical projection neurons. The SPG15 iPSC-derived neurons exhibited reduced ATP production compared to control neurons, indicating mitochondrial dysfunction in spastizin-deficient neurons. Also, given increased fragmentation of mitochondria in SPG15 neurons, we examined whether restoring mitochondrial morphology dynamics using P110, a peptide inhibitor of the mitochondrial fission protein DRP1, could protect SPG15 neurons. Indeed, treatment with P110 significantly suppressed the accumulated axonal swellings in SPG15 neurons. Further examination of the underlying mechanisms revealed that P110 restored mitochondrial morphology, ameliorated mitochondrial oxidative stress, and improved mitochondrial health, but it did not affect necrosis-related membrane integrity, suggesting specific targeting of mitochondrial deficits by P110. Furthermore, P110 significantly mitigated disease-related apoptosis in SPG15 neurons. Collectively, these findings reveal that restoring mitochondrial morphology and function using P110 lessens mitochondrial oxidative stress and mitigates degeneration of SPG15 neurons, offering a novel therapeutic approach for SPG15.

Keywords:  Apoptosis; Axonal degeneration; Hereditary spastic paraplegias; Mitochondrial dysfunction; SPG15; iPSCs

DOI:  https://doi.org/10.1016/j.nbd.2025.107174
Mol Biol Cell. 2025 Nov 05. mbcE25040182

Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans.

Yuan Li, Jie Zhang, Meijiao Li, Lujia Yang, Xiaochen Wang.

The maintenance of lysosome membrane integrity is vital for cell homeostasis and viability, but the underlying mechanisms are not well understood. In this study, we identified a novel role of SPHK-1, the sole C. elegans sphingosine kinase, in protecting lysosome membrane integrity. Loss of SPHK-1 affects lysosomal integrity and degradative function, causing cargo accumulation and lysosome membrane rupture. sphk-1(lf) mutants show severe defects in embryonic and larval development and have significantly shortened lifespan. We found that sphk-1(lf) mutants accumulate high levels of sphingosine, predominantly in lysosomes. Accordingly, sphingosine supplementation leads to appearance of damaged lysosomes in wild-type worms. We identified sptl-1 and sptl-3 mutations that fully suppress the lysosomal integrity defects in sphk-1(lf) mutants. sptl-1 and sptl-3 encode serine palmitoyltransferases that catalyze the first and rate-limiting step of de novo sphingolipid synthesis. Loss of sptl-1 alleviates sphingosine accumulation, reverses lysosomal integrity and degradation defects, and restores normal development and longevity in sphk-1(lf) mutants. Our study indicates that sphingolipid metabolism via sphingosine kinase is important for maintaining lysosome membrane integrity and function, and is essential for animal development and longevity.

DOI: https://doi.org/10.1091/mbc.E25-04-0182
J Vis Exp. 2025 Oct 14.

Microfluidic Chip for Axonal Injury Models Construction and Enabling Multi-Omics Analysis.

Bing Zhou, Ruixuan Liu, Jiaxin Sun, Maoliang Lu, Qianwen Zhang.

Neurons polarize to form dendrites and axons, enabling intercellular communication. Axonal injury disrupts these connections and transmits damage signals to the soma, often leading to neuronal degeneration. Thus, maintaining axonal homeostasis is essential for promoting local axon regeneration and protecting against neurodegeneration. This process relies on cellular metabolism to supply energy and biosynthetic precursors and is sustained by mechanisms that regulate metabolic balance and eliminate by-products. However, neuronal metabolism is compartmentalized between the soma and axon and is further influenced in vivo by the surrounding microenvironment, such as astrocyte-derived metabolic activity (e.g., the astrocyte-neuron lactate shuttle). These factors complicate the investigation of neurons' intrinsic metabolic mechanisms. To address these challenges, here we developed a microfluidic platform for culturing primary cortical neurons in vitro that preserves key metabolic characteristics observed in vivo, including physiological glycolytic flux and mitochondrial respiration. This system provides a simplified model for investigating intrinsic metabolic remodeling in neurons after axonal injury. Conventional microfluidic chips support in vitro axonal injury models and are compatible with live-cell imaging, immunofluorescence staining, and hypoxia treatment. To accommodate large-scale transcriptomic and metabolomic analyses involving millions of cells, we further designed and fabricated high-throughput microfluidic chips with optimized operational protocols. The device features alternately arranged soma and axon chambers connected by microchannels, and axonal injury is induced by vacuum aspiration of fluid from the axon compartment. This platform enables rapid assessment of metabolite and enzyme dynamics, improving the accuracy and reproducibility of multi-omics investigations.

DOI: https://doi.org/10.3791/68915
Front Pharmacol. 2025 ;16 1693805

The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.

Hassan H Alhassan, Komal Janiyani, Malvi Surti, Mohd Adnan, Mitesh Patel.

  Glycogen Synthase Kinase-3 Beta (GSK3β), a multifunctional serine/threonine kinase, plays a central role in cellular signaling pathways and autophagy regulation, processes critical to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). Dysregulation of autophagy leads to the toxic accumulation of misfolded proteins and damaged organelles, contributing to neuronal loss in these disorders. This review explores the mechanistic interplay between GSK3β and autophagy, highlighting its modulation through key pathways, including mTOR, AMPK and Bcl-2 and its direct impact on autophagy-related proteins such as Beclin-1 and LC3. This review systematically discusses the disease-specific roles of GSK3β in autophagy dysregulation and protein aggregation, providing evidence from recent studies on neurodegenerative models. Additionally, therapeutic approaches targeting GSK3β are evaluated, including preclinical and clinical trials of GSK3β inhibitors and combination therapies with autophagy modulators, emphasizing their potential for improving neuroprotection and cellular homeostasis. Despite its promise, challenges such as off-target effects and pathway complexity remain significant. This review highlights the importance of GSK3β as both a therapeutic target and a biomarker, offering avenues for future research into selective GSK3β modulators that enhance autophagy and mitigate ND progression.

Keywords:  autophagy; cellular homeostasis; glycogen synthase kinase-3 beta; neurodegenerative diseases; protein aggregation

DOI:  https://doi.org/10.3389/fphar.2025.1693805
Acta Neuropathol Commun. 2025 Nov 07. 13(1): 228

Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.

Martin J Berg, Veeranna, Corrinne M Rosa, Asok Kumar, Panaiyur S Mohan, Philip Stavrides, Sandipkumar Darji, Deanna M Marchionini, Dun-Sheng Yang, Ralph A Nixon.

   BACKGROUND: Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington's disease (HD). Stimulating autophagy may enhance clearance of mHTT and its aggregates which has been considered as a possible therapeutic strategy. However, the role and competence of the autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown.
METHODS: Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex or cerebellum of HD brains staged from Grade HD2 to HD4 by Vonsattel neuropathological criteria compared to controls.
RESULTS: Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins sequestosome 1 (p62/SQSTM1) and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. In addition, cargo-loaded autophagosomes and cathepsin-positive autolysosomes were readily observed, implying a lack of significant blockage in autophagosome formation and autophagosome-lysosome fusion.
CONCLUSIONS: The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but the observed progressive HTT build-up and AL accumulation at advanced disease stages may signify a failure in autophagy substrate clearance. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, could lead to therapeutic benefits in HD patients.

Keywords:  Autophagy; Human brain; Huntington’s disease; Lysosome; Pathobiology

DOI:  https://doi.org/10.1186/s40478-025-02131-8
Cell Death Dis. 2025 Nov 04. 16(1): 791

Loss of Fanconi anemia proteins causes a reliance on lysosomal exocytosis.

Becky Xu Hua Fu, Albert Xu, Hua Li, Daniel E Johnson, Jennifer R Grandis, Luke A Gilbert.

Mutations in the Fanconi Anemia (FA) pathway lead to a rare genetic disease that increases risk of bone marrow failure, acute myeloid leukemia, and solid tumors. FA patients have a 500 to 800-fold increase in head and neck squamous cell carcinoma compared to the general population and the treatments for these malignancies are ineffective and limited due to the deficiency in DNA damage repair. Using unbiased CRISPR-interference screening, we found the loss of FA pathway function renders cells dependent on key exocytosis genes such as SNAP23. Further investigation revealed that loss of FA pathway function induced deficiencies in lysosomal health, dysregulation of autophagy and increased lysosomal exocytosis. The compromised cellular state caused by the loss of FA genes is accompanied by decreased lysosome abundance and increased lysosomal membrane permeabilization in cells. We found these signatures in vitro across multiple cell types and cell lines and in clinically relevant FA patient cancers. Our findings are the first to connect the FA pathway to lysosomal exocytosis and thus expands our understanding of FA as a disease and of induced dependencies in FA mutant cancers.

DOI: https://doi.org/10.1038/s41419-025-08164-0
Neuromolecular Med. 2025 Nov 05. 27(1): 73

Glutamic Acid at Position 168 Is a Constitutive Activator of Tank Binding Kinase 1 Catalytic Function.

Noopur Bhore, Anubhuti Sarkar, Zhi Yao, Susanne Herbst, Patrick A Lewis.

  TANK binding kinase 1 (TBK1) is serine/threonine protein kinase member of the inhibitor of nuclear factor-kB kinase family, with links to the etiology of familial as well as idiopathic Amyotrophic Lateral Sclerosis. It contributes to several regulatory cellular processes such as autophagy, inflammation and apoptosis. Reduction or loss of TBK1 kinase activity is associated with increased risk of ALS, and so understanding the molecular basis of this activity is an important research priority. In this current study, the role of the E168 residue, located adjacent to the active site of TBK1, has been assessed using a combination of artificial and naturally occurring variants found at this codon - evaluated using multiple readouts for TBK1 kinase activity. The results suggest that the negative charge resulting from the presence of a glutamic acid at this codon is a constitutive activator of TBK1 activity.

Keywords:  ALS; Kinase; Kinase activity; Mutations; P62; Phosphorylation; RAB7; TBK1

DOI:  https://doi.org/10.1007/s12017-025-08894-6
J Integr Neurosci. 2025 Oct 29. 24(10): 43165

Herkinorin Promotes μ-Opioid Receptor Internalization and Protects iPSC-Derived Neurons from Hypoxic/Ischemic Injury.

Zhihai Ju, Guyan Wang, Yanhong Yan, Xuan Liang, Xu Cui.

   BACKGROUND: Hypoxic/ischemic brain injury remains a major clinical challenge, yet the cellular mechanisms linking oxygen-glucose deprivation/reperfusion (OGD/R) to opioid receptor regulation in human neurons are still not fully understood. The trafficking of μ-opioid receptors (MOR) and κ-opioid receptors (KOR) is a key regulator of neuronal survival under stress. Most studies to date in this field have employed rodent models. However, given the molecular and physiological differences between rodents and humans, this study employed human induced pluripotent stem cell (iPSC)-derived neurons to investigate opioid receptor trafficking during OGD/R, as well as the neuroprotective effects of Herkinorin.
METHODS: Human iPSC-derived neurons were subjected to 2 h of OGD followed by 24 h of reoxygenation. Cells were treated with Herkinorin (0.1, 0.5, or 1 μM) during OGD/R. Apoptosis was assessed using flow cytometry, while the localization of MOR and KOR in membrane and cytoplasmic fractions was analyzed using western blotting. Western blotting was also used to quantify the expression of apoptosis-related proteins Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and cleaved Caspase-3. Statistical comparisons were performed using one-way ANOVA with Tukey's post hoc test or non-parametric equivalents.
RESULTS: OGD/R significantly increased neuronal apoptosis, upregulated pro-apoptotic Bax and cleaved Caspase-3, and downregulated anti-apoptotic Bcl-2. These changes were accompanied by altered distribution of MOR, but not KOR localization, specifically decreasing cytoplasmic MOR while maintaining membrane levels. Herkinorin, particularly at 1 μM, induced redistribution of MOR from the plasma membrane to cytoplasm, consistent with receptor internalization; it also significantly reduced apoptosis in a concentration-dependent manner. Furthermore, treatment with Herkinorin reversed the OGD/R-induced molecular changes by decreasing the expression of Bax and cleaved Caspase-3, while increasing that of Bcl-2. KOR trafficking remained largely unchanged under all conditions. Importantly, Herkinorin concentrations above 10 μM reduced neuronal viability, indicating a narrow therapeutic window.
CONCLUSIONS: Herkinorin exerts neuroprotective effects in human iPSC-derived neurons subjected to OGD/R, potentially by modulating MOR internalization and influencing mitochondrial-dependent apoptotic pathways. However, its efficacy is restricted to a limited dose range (0.1-1 μM), as higher concentrations are toxic. The receptor subtype-specific trafficking pattern observed in this study underscores the importance of human-relevant models for mechanistic and translational research on opioid receptors.

Keywords:  Herkinorin; apoptosis; brain ischemia; induced pluripotent stem cells; neuroprotection; opioid receptors, kappa; opioid receptors, mu; receptor internalization

DOI:  https://doi.org/10.31083/JIN43165
EMBO J. 2025 Nov 03.

Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons.

Yu Feng, Tongshu Luan, Zhenda Zhang, Wei Wang, Yuanyuan Chu, Sijia Wan, Xiaorong Pan, Jie Li, Yifan Liu, Yaqian Xu, Kun Dou, Tong Wang.

  Directed axonal trafficking of mRNA via ribonucleoprotein (RNP) complexes is essential for neuronal function and survival. However, mechanisms governing retrograde RNP transport remain poorly understood. Here, we reveal that Annexin A7 (ANXA7) promotes the recruitment of aggregation-prone T-cell intracellular antigen 1 (TIA1)-containing RNPs to cytoplasmic dynein, enabling their retrograde trafficking to the soma for degradation. Both persistent and transient Ca²⁺ elevation disrupted this function of ANXA7, leading to the detachment of TIA1 granules from dynein, impairing their transport, and subsequently triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, preventing their transport and inducing pathological aggregation of TIA1, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression reinforces trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. We describe here a Ca2+ -regulated mechanism which modulates retrograde axonal trafficking of RNPs and prevents the formation of pathological aggregates in axons.

Keywords:  Axon Trafficking; Calcium Signaling; Dynein; Phase Separation; Protein Aggregates

DOI:  https://doi.org/10.1038/s44318-025-00609-8
Sci China Life Sci. 2025 Nov 06.

Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β.

Jun Ren, Yiliang Xu, Lin Yuan, Yingxin Liu, Qian Chu, Tian Zhao, Wei Zhang, Jing Tian, Shi-Qiang Wang, Haihong Ye.

  Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, encodes a multifunctional protein implicated in various aspects of neuronal development. However, the precise role of DISC1 in neuronal polarization has remained elusive. Here, we show that dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons. Expression of phosphodead human DISC1 (hDISC1AA) delays the morphological transition from multipolar to uni/bipolar stages in mouse cortical neuronal cultures. hDISC1AA-knockin mice exhibit misoriented axon initial segments of cortical projecting neurons, reduced corpus callosum thickness, and schizophrenia-like behavior. Moreover, GSK3β activity is increased in the cortices of these knockin mice, and embryonic administration of GSK3β inhibitor effectively rescues aberrant axon initial segment and corpus callosum, as well as their behavioral deficits. Our findings support a molecular model wherein dephosphorylation of DISC1 at both Ser58 and Ser713 leads to enhanced GSK3β activity and subsequent inhibition of axon formation, potentially representing a key pathogenic mechanism underlying psychiatric disorders related to DISC1 dysfunction.

Keywords:  DISC1; GSK3β; neuronal polarization; phosphorylation; schizophrenia

DOI:  https://doi.org/10.1007/s11427-025-3033-9
Trends Neurosci. 2025 Nov 06. pii: S0166-2236(25)00219-X. [Epub ahead of print]

Rethinking neurodegeneration through a co-proteinopathy lens.

Yu P Zhang, Shekhar Kedia, David Klenerman.

  Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; coaggregation; protein aggregation; proteostasis

DOI:  https://doi.org/10.1016/j.tins.2025.10.006
J Neurochem. 2025 Nov;169(11): e70270

Leveraging Proteomics to Explore the Molecular Mechanisms of Primary Tauopathies.

Laura Nementzik, Tomas Kavanagh, Sian Genoud, Eleanor Drummond.

  Primary tauopathies are progressive neurodegenerative diseases characterised by the deposition of aggregated tau in the brain. The molecular mechanisms underlying tau toxicity and neurodegeneration in these diseases are still poorly understood. Proteomics studies of human primary tauopathy brain tissue are beginning to provide insight into molecular mechanisms involved in disease pathogenesis. Here, we review the current landscape of human brain proteomics in three primary tauopathies: progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. For progressive supranuclear palsy, the most well-studied primary tauopathy, we provide a combined analysis of bulk proteomic changes in the brain. From this compilation and additional studies using complementary proteomics approaches, we highlight five highly relevant disease mechanisms in primary tauopathies: mitochondrial dysfunction, synaptic impairment, autophagy and endolysosomal dysfunction, RNA and RNA-binding protein dysregulation, and iron dyshomeostasis. We discuss how each of these mechanisms participates in primary tauopathy pathogenesis and suggest recommendations for future proteomics studies that will advance our understanding of these diseases.

Keywords:  RNA‐binding proteins; autophagy; corticobasal degeneration; ferritin light chain; mitochondria; pick's disease; progressive supranuclear palsy; proteomics; synapse; tauopathy

DOI:  https://doi.org/10.1111/jnc.70270
Invest Ophthalmol Vis Sci. 2025 Nov 03. 66(14): 2

USH2A-Mutated Human Retinal Organoids Model Rod-Cone Dystrophy.

Kristen E Ashworth, Jiajie Zhang, Cassandra D'Amata, Elise Héon, Brian G Ballios.

Purpose: USH2A mutations are the leading cause of autosomal recessive retinitis pigmentosa (RP), a progressive blinding disease marked by photoreceptor degeneration. Animal models fail to recapitulate the features of USH2A RP seen in humans, and its earliest pathogenic events remain unknown. Here, we established a human model of USH2A RP using retinal organoids derived from patient induced pluripotent stem cells and CRISPR-Cas9-engineered isogenic-USH2A-/- induced pluripotent stem cells.
Methods: We assessed organoids for cellular, molecular, and morphological defects using serial live imaging and whole organoid and fixed section analyses.
Results: Both patient-derived and isogenic-USH2A-/- organoids showed preferential rod photoreceptor loss followed by widespread degeneration, consistent with the clinical phenotype. Additionally, isogenic-USH2A-/- organoids showed early defects in proliferation and structure.
Conclusions: Our findings suggest that molecular changes precede overt photoreceptor loss in USH2A RP, and pathogenesis may begin before clinical symptoms emerge. By defining early and late disease features, we provide new insight on the developmental origins of USH2A RP to guide therapeutic strategies.

DOI: https://doi.org/10.1167/iovs.66.14.2
Amyotroph Lateral Scler Frontotemporal Degener. 2025 Nov 06. 1-10

Unraveling the genetic landscape of ALS in Greece: identification of known and novel causative variants in a 353-patient cohort.

Chrisoula Kartanou, Zoi Kontogeorgiou, Theodoros Loupis, Dimitrios M Vrachnos, Nikolaos Ragazos, Ifigenia Spyropoulou, Maria Petraki, Chrysoula Koniari, Stavroula Aristeidou, Eleftheria Koropouli, Ariadne Daponte, Michail Rentzos, Elisabeth Kapaki, Marios Panas, Periklis Makrythanasis, Leonidas Stefanis, Georgios Koutsis, Georgia Karadima.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, fatal neurodegenerative disorder characterized by progressive loss of motor neurons. Approximately 15% of individuals diagnosed with ALS have a known genetic variant that contributes to disease. Herein, we present clinical and genetic data of a large Greek ALS cohort.
PATIENTS AND METHODS: The cohort consisted of 353 Greek consecutive index patients with ALS, including 16 patients with related motor neuron disease (MND) subtypes (nine with PLS, four with PBP, and three with PMA). Next generation sequencing raw data (obtained from the NYGC ALS Consortium) were further analyzed and used to screen for causative variants in known implicated genes. Repeat expansions in C9ORF72 and ATXN2 were investigated using ExpansionHunter software, repeat-primed PCR and fragment analysis.
RESULTS: Pathogenic repeat expansions in C9ORF72 were detected in 41 patients (11.6%). In addition, 30 patients (8.5%) carried a causative variant in one of the genes studied. Known causative variants were identified in 27 cases (nine in SQSTM1, seven in TARDBP, five in SOD1, three in NEK1 and one each in SETX, VCP, FUS), whereas novel causative variants were identified in three cases (SOD1, FIG4, TBK1). In total, 71 cases received a molecular genetic diagnosis (20.1%). Additionally, seven cases (2.0%) carried an intermediate repeat expansion (30-33 CAG) in ATXN2.
CONCLUSION: Our results reveal the distinct genetic profile of Greek ALS patients. These findings will have an impact on genetic counseling, the design of diagnostic gene panels for the Greek population and on genotype-specific therapeutic interventions. Understanding the genetic causes of ALS in different populations is becoming increasingly important, especially with the advent of personalized medicine.

Keywords:  Amyotrophic lateral sclerosis (ALS); C9ORF72 repeat expansions; Greek population; causative variants; next generation sequencing (NGS)

DOI:  https://doi.org/10.1080/21678421.2025.2582828
J Neurochem. 2025 Nov;169(11): e70290

The Role of DEAF1 in Dendritic and Synaptic Development: Insights Into Neurodevelopmental Disorders.

Takuma Nishijo, Hidenori Ito, Nanako Hamada, Yasushi Kishimoto, Koh-Ichi Nagata.

  DEAF1 functions as both a transcriptional activator and repressor and is implicated in neurodevelopmental disorders (NDDs); however, its role in neuronal development remains poorly understood. In this study, we investigated the role of DEAF1 in cortical development, with a particular focus on neuronal architecture, as well as its contributions to synaptic function and neuronal activity. In vitro analyses revealed that dendritic development, but not axonal development, was inhibited in DEAF1-deficient hippocampal neurons. Using in utero electroporation-based acute knockdown experiments, we further demonstrated that DEAF1 knockdown in post-migratory mouse cortical neurons leads to impaired dendritic arborization and reduced dendritic spine density, without significantly affecting neuronal migration or axonal extension. These findings suggest that DEAF1's primary role in neurodevelopment is associated with the later stages of cortical maturation, specifically in dendritic and synaptic development. Additionally, electrophysiological analyses revealed that DEAF1 knockdown reduces both excitatory and inhibitory synaptic transmission. Furthermore, neuronal excitability was significantly reduced, suggesting a potential dysfunction in voltage-gated sodium and/or potassium channels. Collectively, our findings reveal a critical role for DEAF1 in dendritic and synaptic development, providing new insights into the cellular and functional mechanisms underlying DEAF1-associated NDDs.

Keywords:  DEAF1; corticogenesis; dendrite dvelopment; neurodevelopmental disorder; synaptogenesis; transcription factor

DOI:  https://doi.org/10.1111/jnc.70290
J Neurochem. 2025 Nov;169(11): e70284

Delivering Progranulin to Astrocytic Lysosomes Promotes Growth of Co-Cultured Neurons.

Azariah K Kaplelach, Justin A Hall, Wren O Nader, Amelia G Davidson, Margaret D Ireland, Lara Ianov, Andrew E Arrant.

  Progranulin (GRN) mutations, most of which cause progranulin haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD). Restoring progranulin to people with GRN mutations is a promising therapeutic strategy and understanding progranulin's mechanism of action may enable the design of optimal progranulin-based therapies. Progranulin is constitutively secreted and interacts with several receptors, but is also taken up and trafficked to lysosomes where it is necessary for maintaining normal lysosomal function. Progranulin promotes neuronal growth and survival, but it is not clear if these actions are mediated by extracellular signaling or by regulation of lysosomal function. In previous work we showed that progranulin acts in neuronal lysosomes to promote neuronal survival. In this study we investigated the mechanism by which progranulin promotes neuronal growth using lentiviral vectors expressing either progranulin (PGRN) or a non-secreted, lysosome-targeted progranulin (L-PGRN) in rat primary hippocampal neurons and astrocytes. Using lentiviral vectors driven by non-selective (PGK), neuron-selective (hSyn), or astrocyte-selective (GFAP) promoters, we found that delivering L-PGRN to astrocytes, but not neurons, promoted dendritic outgrowth in primary hippocampal cultures. L-PGRN-transduced astrocytes grown on transwell inserts also promoted the growth of co-cultured neurons. RNA sequencing of astrocytes indicated that L-PGRN downregulated transcriptomic pathways associated with cellular reactivity. Analysis of astrocyte conditioned medium showed that transduction with L-PGRN reduced the secretion of PAI-1, a protease inhibitor that inhibits neuronal outgrowth in hippocampal cultures. Collectively, these data indicate that delivering progranulin to astrocytic lysosomes may inhibit the secretion of factors that restrain neuronal outgrowth. Consistent with this hypothesis, depleting astrocytes from hippocampal cultures increased dendritic outgrowth and occluded the pro-growth effects of L-PGRN. These data show that under these culture conditions, progranulin secretion is not required to promote dendritic outgrowth. Instead, progranulin increased dendritic outgrowth by a non-cell autonomous mechanism involving actions in astrocytic lysosomes. These data add to a growing body of evidence that progranulin may act on astrocytes to promote neuronal health.

Keywords:  astrocyte; frontotemporal dementia; lysosome; progranulin

DOI:  https://doi.org/10.1111/jnc.70284
J Cereb Blood Flow Metab. 2025 Nov 07. 271678X251389379

An iPSC-derived model for drug screening in cerebral small vessel disease.

Alessandra Granata, Maha Al-Thani, Mary Goodwin-Trotman, David M Smith, Tom Van Agtmael, Hugh S Markus.

  Despite the enormous health importance of cerebral small vessel disease (cSVD) there are few treatments available. A major limitation in screening new therapies is a lack of clinically relevant disease models. Induced pluripotent stem cell (iPSC) technology allows creation of in vitro models of the vascular unit, which is found to be affected in cSVD. Here we derived iPSC from skin biopsies obtained from patients with two of the most common monogenic forms of cSVD, HTRA1 mutations and COL4A1/2 mutations. iPSCs were differentiated into brain endothelial-like cells and mural cells and co-cultured in a transwell system to replicate the vascular unit. iPSC models derived from the two distinctive forms of monogenic cSVD demonstrated a common molecular phenotype characterised by tight junction defects, elevated actin stress fiber expression and mural cell loss, increased blood-brain barrier (BBB) permeability and elevated matrix metalloproteinase (MMP) levels. Moreover, the model was successfully optimised to a 96-well format to screen 13 MMP inhibitors, three of which effectively restored permeability to control levels. Our findings provide evidence that MMP inhibition could serve as a potential therapeutic strategy for cSVD as well as present a robust model to screen drugs in cSVD.

Keywords:  Cerebral small vessel disease; drug screening; induced pluripotent stem cells; matrix metalloproteinases; vascular dementia

DOI:  https://doi.org/10.1177/0271678X251389379
Genes Cells. 2025 Nov;30(6): e70063

Cell Surface LAMP-2C Is Internalized in a Clathrin-Dependent Manner and Transported to the Recycling and Lysosomal Pathways.

Hiroshi Sakane, Yuna Takeda, Ikuto Okuda, Kanae Michihara, Kenji Akasaki.

  Lysosomes are acidic organelles that degrade a diverse range of substrates, and lysosome-associated membrane protein (LAMP)-1 and LAMP-2 are the major lysosomal membrane components. Three LAMP-2 splice variants have been identified, namely, LAMP-2A, LAMP-2B, and LAMP-2C. We previously demonstrated that when mouse LAMP-2C was stably expressed in HEK293 cells, a portion of it was present on the plasma membrane. LAMP-2C possesses a tyrosine-based motif that functions as a signal for lysosomal targeting and clathrin-mediated endocytosis (CME). However, whether cell surface LAMP-2C is indeed internalized via CME has not been clearly defined. If this occurs, it is unknown whether internalized LAMP-2C returns to the cell surface and/or moves to lysosomes from early endosomes. In this study, we found that cell surface LAMP-2C was internalized, and its internalization was impaired by knockdown of the clathrin heavy chain or the medium subunit of adaptor protein complex 2. Internalized LAMP-2C was transported to early endosomes, and a portion of the internalized LAMP-2C was recycled back to the plasma membrane. Furthermore, immunofluorescence and subcellular fractionation showed that the internalized LAMP-2C was transported to lysosomes. These results suggest that cell surface LAMP-2C is internalized by CME and that internalized LAMP-2C enters the recycling and lysosomal pathways.

Keywords:  LAMP‐2; clathrin; lysosome; recycling

DOI:  https://doi.org/10.1111/gtc.70063
PLoS Genet. 2025 Nov 07. 21(11): e1011941

Functional role for cas cytoplasmic adaptor proteins during cortical axon pathfinding.

Jason A Estep, Alyssa M Treptow, Payton A Rao, Patrick Williamson, Wenny Wong, Martin M Riccomagno.

Proper neural circuit organization requires individual neurons to project to their targets with high specificity. While several guidance molecules have been shown to mediate axonal fasciculation and pathfinding, less is understood about how neurons intracellularly interpret and integrate these cues. Here we provide genetic evidence that the Crk-Associated Substrate (Cas) family of intracellular adaptor proteins is required for proper fasciculation and guidance of two cortical white matter tracts: the Anterior Commissure (AC) and thalamocortical axons (TCAs). Using a Cas Triple Conditional Knock Out (Cas TcKO) mouse model, we show that Cas proteins are required for proper TCA projection by a non-neuronal cortical cell population. We also demonstrate a requirement of the β1-integrin receptor for TCA projection, similarly in a population of non-neuronal cortical cells. Additional analysis of Cas TcKO mutants reveals a role for Cas proteins in AC fasciculation, here within the neurons themselves. This AC fasciculation requirement is not phenocopied in β1-integrin deficient mutants, suggesting that Cas proteins might signal downstream of a different receptor during this axon pathfinding event. These findings implicate Cas proteins as key mediators of cortical axon tract fasciculation and guidance.

DOI: https://doi.org/10.1371/journal.pgen.1011941
Adv Biol (Weinh). 2025 Nov 05. e00486

A Hierarchical Cascade of Organellar Silencing and Their Regeneration Under Anaesthetic Stress in Plants.

Shilpa Chandra, Sakshi Chouhan, Bodhidipra Mukherjee, Abdul Salam, Chayan Kanti Nandi, Laxmidhar Behera.

  Anaesthetics temporarily inhibit neural activity by acting on voltage-gated sodium channels and GABA receptors. Although their neurological mechanisms are well-defined, their wider cellular effects, especially in non-neuronal systems, are inadequately understood. This study utilized Solanum lycopersicum plant's root apex cells as a transparent model to examine anaesthetic-induced subcellular alterations via live-cell fluorescence imaging, immunostaining, and super-resolution microscopy. These findings demonstrate the hierarchical cascade of organelle dysfunction, such as mitochondria, lysosomes, vesicle trafficking, and nuclear architectures under anaesthesia in plants. The nucleus is identified as the main controller of recovery potential and cellular fate. In a time dependent experiment, it is found that plant cells exposed to lidocaine for up to 4 h can still recover mitochondrial potential, lysosomal function, and nuclear integrity when anaesthesia is removed. However, beyond 4 h the damage, especially to the nucleus, is irreversible, and cells proceeded to cell death. The data further demonstrate that organelles can recover after brief exposure, but prolonged exposure stops recovery, resulting in the irreversible degradation of the nucleus leading to complete cell death. The results may help to uncover organelle-related dysfunction under anaesthetic toxicity and provide a clearer understanding for minimizing or reversing such damage.

Keywords:  anaesthesia; hierarchical cascade; nuclear reorganization; organelle recovery; root apex

DOI:  https://doi.org/10.1002/adbi.202500486
Neurobiol Dis. 2025 Oct 30. pii: S0969-9961(25)00384-5. [Epub ahead of print] 107167

Perspectives on the utilization of cell-free DNA in amyotrophic lateral sclerosis (ALS) diagnostics and prognostics - insight from cancer research.

Anna Konopka.

  Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disease with limited diagnostic and prognostic tools. In recent years, cell-free DNA (cfDNA) has emerged as a promising non-invasive biomarker in various clinical settings, particularly in oncology. Despite its potential, the application of cfDNA in ALS is still in its early stages, and several critical gaps must be addressed. This discussion article reviews the current knowledge about cfDNA in ALS and explores its potential applications for disease diagnosis, monitoring, and prognosis. Drawing on the advances made in cancer research, it also examines the challenges that ALS research may face in cfDNA utilization, highlighting lessons learned from oncology. Taken together, these insights point to the urgent need for a comprehensive understanding of cfDNA characteristics specific to ALS. Given the current lack of reliable diagnostic and prognostic biomarkers in ALS, further investigation into cfDNA represents a valuable and necessary scientific endeavor with the potential to transform patient care and disease management.

Keywords:  ALS; Biomarkers; Cancer; cfDNA

DOI:  https://doi.org/10.1016/j.nbd.2025.107167
Nat Commun. 2025 Nov 07. 16(1): 9833

Lysosomal and mTORC1 signaling dysregulation underpin the pathology of spastic paraplegia type 80.

Yiqiang Zhi, Tongtong Zhang, Danping Lu, Shuhuai Lin, Huizhen Su, Yupei Wu, Qiyuan Chang, Shuyuan Wang, Chenning Lv, Honggao Fu, Li-Yu Chen, Wan-Jin Chen, Ning Wang, Zhifei Fu, Xiang Lin, Dan Xu.

Endosomal sorting complex required for transport (ESCRT) is the major membrane remodeling complex, closely associated with endolysosomal repair and hereditary spastic paraplegias (HSP) diseases. Loss of function mutations in the ESCRT-I component UBAP1 causes a rare type of HSP (spastic paraplegia 80, SPG80), while the underlying pathological mechanism is unclear. Here, we found that UBAP1 but not SPG80 causing mutant was efficiently recruited to damaged lysosomes and mediated lysosome recovery. Loss of UBAP1 results in dysfunction of lysosomes, disconnecting mTOR localization on lysosomes, leading to cytoplasmic mTORC1 activation and TFEB dephosphorylation, as confirmed in vitro and in vivo models. Administration of rapamycin, a specific inhibitor of mTORC1, enhances mTOR lysosomal localization and TFEB phosphorylation. This pharmacological intervention effectively attenuated disease progression and restored lysosomal homeostasis in Ubap1 deficiency mice. Our findings reveal UBAP1's role in lysosome regulation and suggest rapamycin may benefit patients with HSP and other motor neuron disorders.

DOI: https://doi.org/10.1038/s41467-025-64800-5
Cell Stem Cell. 2025 Nov 03. pii: S1934-5909(25)00374-1. [Epub ahead of print]

A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders.

Lu Wang, Yuji Nakamura, Junhao Li, David Sievert, Yang Liu, Toan Nguyen, Prudhvi Sai Jetti, Ethan Thai, Rachel Yibei Zhou, Jiaming Weng, Naomi Meave, Manya Yadavilli, Robyn Howarth, Kevin Camey, Niyati Banka, Charlotte Owusu-Hammond, Chelsea Barrows, Stephen F Kingsmore, Maha S Zaki, Eran Mukamel, Joseph G Gleeson.

  Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.

Keywords:  brain organoids; epilepsy; intellectual disability; microcephaly; neurodevelopmental disease; polymicrogyria; single-cell sequencing

DOI:  https://doi.org/10.1016/j.stem.2025.10.006
Front Mol Neurosci. 2025 ;18 1639114

Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.

Zhanguo Su, Lijuan Xiang.

  The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.

Keywords:  ER stress; exercise; muscle function; neurodegenerative diseases; unfolded protein response

DOI:  https://doi.org/10.3389/fnmol.2025.1639114
Autophagy Rep. 2025 ;4(1): 2574355

CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes.

Elisa Fasana, Ilaria Fregno, Maurizio Molinari.

  Membrane contact sites (MCS) between organelles maintain the proximity required for controlled exchange of small molecules and ions yet preventing fusion events that would compromise organelles' identity and integrity. Here, by investigating the intracellular fate of the disease-causing Z-variant of alpha1 antitrypsin (ATZ), we report on a novel function of MCS between the endoplasmic reticulum (ER) and RAB7/LAMP1-positive endolysosomes in ER-to-lysosome-associated degradation (ERLAD). For this function, the VAPA:ORP1L:RAB7 multi-protein complex forming MCS between the ER and endolysosomes engages, in an ERLAD client-driven manner, the misfolded protein segregation complex formed by the lectin chaperone calnexin (CNX), the ER-phagy receptor FAM134B, and the ubiquitin-like protein LC3. Generation of this supramolecular complex facilitates the membrane fusion events regulated by the SNARE proteins STX17 and VAMP8 that ensure efficient delivery of ATZ polymers from their site of generation, the ER, to the site of their intracellular clearance, the degradative RAB7/LAMP1-positive endolysosomes.

Keywords:  Calnexin (CNX); ER-phagy; ER-to-Lysosome-Associated Degradation (ERLAD); Endoplasmic Reticulum (ER); FAM134B; Membrane Contact Sites (MCS); ORP1L; RAB7; VAPA; endolysosomes

DOI:  https://doi.org/10.1080/27694127.2025.2574355
Trends Cell Biol. 2025 Nov 06. pii: S0962-8924(25)00225-9. [Epub ahead of print]

Membrane curvature at the ER-PM contact sites.

Yang Yang, Luis A Valencia, Bianxiao Cui.

  Membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) are essential for lipid transfer, calcium signaling, and membrane organization. While the formation and function of ER-PM contacts are increasingly well-characterized, the spatiotemporal regulation of their localization remains elusive. Emerging evidence using nanopatterned substrates, ultrastructural imaging, and protein localization analyses indicates that membrane curvature can act as a spatial cue for the recruitment of specific tethering proteins, influencing where contact sites form. This opinion article synthesizes recent advances linking membrane topography ER-PM contact organization and highlights systems where curvature actively orchestrates contact position through curvature-sensing proteins. It also outlines key unanswered questions about how membrane curvature integrates into broader signaling networks that govern organelle contact communication.

Keywords:  ER–PM contact; RyR2; calcium signaling; junctophilin; membrane curvature

DOI:  https://doi.org/10.1016/j.tcb.2025.10.002
Cell Death Discov. 2025 Nov 03. 11(1): 499

FBXW7-mediated CHK2 regulation modulates DNA damage response and cellular stability in Huntington's disease.

Tae Eun Kang, Yu Min Lee, Seung Ho Choi, KyoungJoo Cho.

DNA damage activates the DNA damage response (DDR) machinery. However, aging impairs DDR in neurons, thereby increasing susceptibility to neurodegenerative diseases, such as Huntington's disease (HD). The mutant huntingtin (mHTT) protein interferes with DNA repair, leading to DNA lesions and a feedback loop of cellular stress that accelerates neurodegeneration. Although the individual roles of FBXW7, ATM, and checkpoint kinase (CHK) are well-known in DDR, their combined roles in HD remain unclear. In this study, we investigated the FBXW7-mediated CHK2 pathway in HD, in which mHTT levels increase, whereas wild-type (WT) HTT levels decrease. HD cells containing mHTT or expanded polyQ-HTT were more prone to DNA damage than cells containing wtHTT or normal-length polyQ, demonstrating the increased vulnerability of HD neurons. Downregulating the expression of FBXW7 reduces susceptibility to DNA damage and promotes cellular stability. Additionally, FBXW7 specifically prevented CHK2 degradation, but not CHK1 degradation. This suggests a selective role in DDR regulation. Thus, the FBXW7-CHK2 pathway may alleviate DNA damage in HD by supporting DDR and inducing cell cycle arrest. The intricate relationship between DDR and HTT is fundamental to the pathophysiology of HD. Elucidating these mechanisms could facilitate the development of new therapeutic strategies that enhance DNA repair or correct DDR dysfunction, thereby slowing disease progression or delaying symptom onset. Understanding this pathway may provide insights into the targeting of DNA repair defects in HD and related neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41420-025-02798-x
J Cell Biol. 2025 Dec 01. pii: e202311040. [Epub ahead of print]224(12):

Bni5 regulates and coordinates septin architecture and myosin-II functions at the cell division site.

Hiroki Okada, Xi Chen, Joseph Marquardt, Kangji Wang, Erfei Bi.

The spatiotemporal coordination of septins and myosin-II in processes like cytokinesis is not well understood. In Saccharomyces cerevisiae, Bni5 links the myosin-II heavy chain Myo1 to the septin hourglass at the bud neck prior to cytokinesis, but the underlying mechanisms and functions remain unclear. Here, we show that Bni5 binds septin filaments, the septin-associated kinase Elm1, and Myo1 via distinct domains. Bni5 regulates the architecture and stability of the septin hourglass until it dissociates from the bud neck at the onset of cytokinesis. This dissociation, facilitated through phosphorylation of Bni5 by Gin4, an Elm1-interacting kinase, enables timely remodeling of the septin hourglass into a double ring. Bni5 also mediates the role of Myo1 in retrograde actin cable flow during polarized growth and ensures maximal accumulation of Myo1 at the bud neck before cytokinesis, reinforcing the actomyosin ring and buffering it against perturbations. These findings establish Bni5 as a key regulator and coordinator of septins and myosin-II at the division site.

DOI: https://doi.org/10.1083/jcb.202311040