bims-axbals 2026-07-26 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–07–26
fifteen papers selected by
TJ Krzystek

VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.
CAST/ELKS-endophilin-A interaction ensures synaptic vesicle pool size.
A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.
Borrowed scissors for lysosome fission.
Inhibition of leucine-rich kinase 2 (LRRK2) promotes peripheral axon regeneration via phosphorylation-network remodelling.
Global cellular responses to lysosomal damage.
USP28 Deficiency is Linked to Impaired Ubiquitin-dependent Proteostasis in Huntington's Disease.
Loss of Atp8a2 drives neurodegeneration through the dysregulation of spatiotemporal phosphatidylserine externalization in mature neurons.
Cellular thermal shift assay of subcellular isolates to evaluate drug-membrane target interactions.
TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.
Molecular Mechanisms Underlying FCCP-Induced Mitophagyin Human Airway Smooth Muscle Cells.
Vps1 drives membrane constriction and fission necessary for endosomal protein sorting.
A human iPSC-derived 3D spinal cord organoid model to study radiation-induced neural injury.
Atg23 prevents aberrant fusion of Atg9 vesicles during delivery to autophagosome formation sites.

Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123

VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.

Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.

  Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.

Keywords:  VAMP7; glia; mitochondrial dynamics

DOI:  https://doi.org/10.1073/pnas.2603069123
Autophagy. 2026 Jul 23.

IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.

Kai-Po Chen, Tz-Chuen Ju.

  Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and γδ T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3β-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.

Keywords:  Autophagy-lysosomal pathway (ALP); glycogen synthase kinase 3B (GSK3B); huntington disease (HD); interleukin 17A (IL17A); transcription factor E3 (TFE3)

DOI:  https://doi.org/10.1080/15548627.2026.2707895
J Cell Biol. 2026 Sep 07. pii: e202508077. [Epub ahead of print]225(9):

CAST/ELKS-endophilin-A interaction ensures synaptic vesicle pool size.

Yasunori Mori, Hirokazu Sakamoto, Yeon-Jeong Kim, Shun Hamada, Fumihiro Kaku, Yamato Hida, Kenzo Hirose, Toshihisa Ohtsuka.

Efficient neurotransmission relies on the precise integration of synaptic vesicle (SV) recycling at the presynaptic terminal. While SV recycling is essential for neurotransmission, the molecular mechanisms coordinating vesicle dynamics at presynaptic terminals remain poorly understood. Here we report that the active zone proteins, CAST and ELKS, play a crucial role in maintaining functional SV pool size through direct interaction with endophilin-A family proteins. In cultured hippocampal neurons, disruption of CAST binding to endophilin-A resulted in a reduced number of SVs available for release, mislocalization of endophilin-A, and altered presynaptic localization of clathrin light chain. Furthermore, reduction of endophilin-A affected expression levels of active zone proteins. Collectively, these findings redefine the role of CAST/ELKS beyond active zone structural organization, demonstrating that their interaction with endophilin-A contributes to maintaining the SV pool required for sustained synaptic transmission at the presynaptic active zone.

DOI: https://doi.org/10.1083/jcb.202508077
Adv Sci (Weinh). 2026 Jul 23. e76778

A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.

Qingjian Xie, Yanbo Zhu, Wenhua Jiang, Haobo Xie, Yaojia Li, Mengjie Hu, Kezheng Li, Huan Yu, Yixuan Pan, Chaoyi Jiang, Xueqin Song, Dongsheng Fan, Binbin Deng.

  Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.

Keywords:  OPTN; PF4; SOD1; amyotrophic lateral sclerosis; mitophagy; proteostasis

DOI:  https://doi.org/10.1002/advs.76778
Nat Cell Biol. 2026 Jul 20.

Borrowed scissors for lysosome fission.

Shawn M Ferguson.

DOI: https://doi.org/10.1038/s41556-026-02028-1
Br J Pharmacol. 2026 Jul 24.

Inhibition of leucine-rich kinase 2 (LRRK2) promotes peripheral axon regeneration via phosphorylation-network remodelling.

Eun-Hae Jang, Eun Mo Yang, Gil Song, Seung Min Park, Harryn Choi, Jaeyong Kim, Chanil Kim, Yunho Gim, Hyuk-Joo Jeon, Yewon Cho, Jong Bae Park, Eun-Mi Hur.

   BACKGROUND AND PURPOSE: In contrast to neurons in the central nervous system, neurons in the peripheral nervous system can regenerate axons after injury via activation of a pro-regenerative transcriptional programme. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, and several small-molecule LRRK2 kinase inhibitors have been developed, with some in clinical trials. However, the physiological role of endogenous, non-pathogenic LRRK2 remains largely unknown.
EXPERIMENTAL APPROACH: LRRK2 expression was examined in murine dorsal root ganglia (DRGs) following sciatic nerve crush (SNC) injury. Regenerative axon growth was assessed using cultured adult DRG neurons after genetic or pharmacological inhibition of LRRK2. Axon regeneration after SNC injury was evaluated in vivo following oral administration of the LRRK2 inhibitors, MLi-2 or PF-06447475. Axonal trafficking experiments and phosphoproteomic analyses were performed to investigate mechanisms underlying axon growth promotion induced by LRRK2 inhibitors.
KEY RESULTS: SNC injury reduced LRRK2 expression in DRGs. Genetic and pharmacological inhibition of LRRK2 enhanced regenerative axon growth in culture. Oral administration of MLi-2 or PF-06447475 promoted axon regeneration in vivo after SNC injury. MLi-2 enhanced mitochondrial trafficking, and phosphoproteomic analyses identified cellular processes and kinase-substrate signalling networks associated with a pro-regenerative state triggered by LRRK2 inhibition.
CONCLUSION AND IMPLICATIONS: These findings identify endogenous, non-pathogenic LRRK2 as a suppressor of axon regeneration. They also support the potential repositioning of small-molecule LRRK2 inhibitors, including clinically advanced compounds and those in preclinical development, as therapeutic strategies to enhance peripheral nerve regeneration.

Keywords:  LRRK2; axon regeneration; dorsal root ganglion; peripheral nerve injury

DOI:  https://doi.org/10.1111/bph.70602
Curr Biol. 2026 Jul 20. pii: S0960-9822(26)00655-X. [Epub ahead of print]36(14): R807-R820

Global cellular responses to lysosomal damage.

Jingyue Jia.

Lysosomes are membrane-bound organelles that orchestrate a wide range of cellular processes, including degradation, metabolism, signaling, gene regulation and quality control, while interacting with other organelles, thereby profoundly shaping cellular homeostasis and fate. Lysosomal membrane integrity is highly vulnerable to a broad spectrum of physiological and pathological insults, acting as both a cause and a consequence of diverse human conditions, including neurodegeneration, cancer, infectious disease and aging. Understanding the mechanisms by which cells respond to lysosomal damage is therefore of critical importance. Recent studies have revealed that cells deploy sophisticated damage response mechanisms locally to repair, remove, and replace damaged lysosomes. In contrast, how local lysosomal damage triggers global cellular responses is only beginning to be understood. This review summarizes recent conceptual advances in global cellular responses to lysosomal damage, encompassing translational, metabolic and transcriptional adaptations, and highlights their crucial roles in restoring cellular homeostasis and shaping outcomes in health and disease.

DOI: https://doi.org/10.1016/j.cub.2026.05.050
Mol Neurobiol. 2026 Jul 20. pii: 780. [Epub ahead of print]63(1):

USP28 Deficiency is Linked to Impaired Ubiquitin-dependent Proteostasis in Huntington's Disease.

Kyoungjoo Cho, Eun Jin Park.

  Huntington's disease (HD) is characterized by mutant huntingtin (mHTT) aggregation and impaired proteostasis; however, upstream regulators of ubiquitin system imbalance remain incompletely understood. This study identified the deubiquitinase USP28 as a potential modulator of ubiquitin-dependent proteostasis in HD. Bulk RNA sequencing of R6/2 mouse brain tissues showed reduced USP28 expression compared with wild-type controls. Consistently, USP28 expression decreased in STHdh striatal cells expressing expanded polyQ huntingtin (Q111). HD cells (STHdh-Q111) exhibited increased accumulation of ubiquitinated proteins and altered ubiquitin turnover, consistent with impaired proteostasis. USP28 overexpression attenuated ubiquitinated protein accumulation and reduced mHTT aggregation, whereas a catalytically inactive USP28 mutant showed limited rescue effects. In addition, USP28 depletion was associated with reduced UBR5 levels, while USP28 restoration partially recovered UBR5 expression in a catalytic activity-dependent manner. Modulation of HECT E3 ligase activity further altered ubiquitination dynamics and mHTT aggregation, suggesting that HECT E3 ligase-related pathways may contribute to proteostasis regulation in HD cells. Collectively, these findings identify USP28 as a proteostasis-associated deubiquitinase reduced in HD models and suggest that USP28 deficiency contributes to ubiquitin burden and mHTT aggregation. Changes in UBR5 expression further point to a potential involvement of HECT E3 ligase-linked ubiquitin regulation, although the direct mechanistic relationship between USP28 and UBR5 remains.

Keywords:  Huntington’s disease; Protein aggregation; Proteostasis; UBR5; USP28; Ubiquitin–proteasome system

DOI:  https://doi.org/10.1007/s12035-026-06073-7
Cell Death Dis. 2026 Jul 22. pii: 652. [Epub ahead of print]17(1):

Loss of Atp8a2 drives neurodegeneration through the dysregulation of spatiotemporal phosphatidylserine externalization in mature neurons.

Adriana Schneider, Alexandra B Merkel, Nunzio Perta, Lisa Ruff, Netta Ussyshkin, Paula Zimmer, Bahar Aksan, Amandine Lepeuve, Laura D'Andrea, Silvia Pelucchi, Elena Marcello, Daniele Di Marino, Daniela Mauceri.

Phosphatidylserine (PS) asymmetry in plasma membranes is critical for cellular functions and serves as an apoptotic signal in many cell types. However, in mature neurons, the molecular mechanisms governing PS distribution, its precise regulation, and its functional significance beyond apoptosis and development remain poorly understood - particularly in the context of neurodegeneration. Here, we mapped the spatiotemporal dynamics of PS exposure in mature hippocampal neurons under physiological and pathological conditions using time-lapse imaging, revealing specific PS externalization hotspots at dendritic branching points. Using multiple in vitro and in vivo neurodegeneration models combined with molecular modeling, RNA interference, pharmacological interventions, and biochemical assays, we identified Atp8a2 as the primary regulator of PS asymmetry in mature neurons beyond its known roles in development. Notably, Atp8a2 expression levels - rather than its flippase activity alone - were essential for maintaining neuronal structural integrity and viability. Atp8a2 expression was significantly altered by neurotoxic stimuli and in multiple mouse models of neurodegeneration. Reduced Atp8a2 expression led to increased PS exposure, compromised neuronal architecture, and heightened susceptibility to degeneration, whereas Atp8a2 overexpression conferred substantial neuroprotection. The distinction between Atp8a2's enzymatic activity and expression level reveals a mechanism of neuronal homeostasis linking PS regulation to structural integrity and survival, possibly through association with cytoskeletal protein networks. Thus, Atp8a2 expression is a critical determinant of mature neuronal viability, presenting a potential target for neuroprotective strategies in neurodegeneration.

DOI: https://doi.org/10.1038/s41419-026-09097-y
MethodsX. 2026 Dec;17 104021

Cellular thermal shift assay of subcellular isolates to evaluate drug-membrane target interactions.

Sahiba K Dogra, Varunya Kattunga, Shona A Mookerjee, Anand Rane, Manish Chamoli, Julie K Andersen.

  The cellular thermal shift assay (CETSA) is a tool for target identification and validation in drug discovery. It relies on thermal melting curves to indicate drug binding and is performed in cells, cell lysates, or purified protein. These approaches can disrupt the structural integrity of membrane proteins, hindering drug-target engagement. We describe the first application of CETSA in isolated mitochondria and show the effects of this approach on the analysis of the compound UK5099 and its known binding target, the mitochondrial pyruvate carrier (MPC), a mitochondrial inner membrane-localized protein complex. Our analysis supports a model in which the MPC must remain structurally intact for UK5099 binding. We demonstrate that the binding of UK5099 to the MPC is disrupted in cells and cell lysates, whereas isolating mitochondria maintains the binding interaction between drug and target observable using CETSA. These data suggest that isolating membrane-bound organelles through subcellular CETSA stabilizes membrane-bound proteins in their native conformation, allowing the identification of membrane-localized drug binding targets that might otherwise be missed.•CETSA on subcellular isolates preserves membrane target in native conformation.•UK5099-MPC binding is preserved in mitochondrial isolates but not cells or lysates.•This approach validates direct-binding interaction of membrane proteins.

Keywords:  Drug discovery; Membrane protein target validation; Mitochondrial pyruvate carrier (MPC); Subcellular compartment isolation

DOI:  https://doi.org/10.1016/j.mex.2026.104021
Cell Rep. 2026 Jul 18. pii: S2211-1247(26)00781-3. [Epub ahead of print]45(7): 117703

TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.

Jiamin Huang, Yayu Wang, Yudong Xu, Yanan Wei, Xiang Yin, Junling Li, Yu Zeng, Meiting Chen, Canjun Li, Li Wang, Xiaomei Li, Lili Qu, Chunlei Cang.

  Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca2+/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.

Keywords:  CLN7; CP: molecular biology; ERK; HSP90; TTYH3; autophagy; chloride conductance; lysosome; lysosome fusion; mTOR; senescence

DOI:  https://doi.org/10.1016/j.celrep.2026.117703
Am J Physiol Lung Cell Mol Physiol. 2026 Jul 23.

Molecular Mechanisms Underlying FCCP-Induced Mitophagyin Human Airway Smooth Muscle Cells.

Sanjana Mahadev Bhat, Oscar A Ramirez Ramirez, Gary C Sieck.

  Mitophagy is a selective autophagic process that eliminates damaged mitochondria, which is essential for mitochondrial quality control and cellular homeostasis. The most extensively characterized mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane (OMM), where it recruits and phosphorylates Parkin at serine 65 (pParkinS65), activating its E3 ligase activity. Active pParkinS65 initiates the ubiquitination (Ub) of OMM proteins resulting in the engulfment and lysosomal degradation of damaged (depolarized) mitochondria. Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial uncoupler, is widely used to experimentally induce mitochondrial depolarization and initiate PINK1-Parkin-dependent mitophagy; however, mitophagic responses to FCCP vary across cell types. In the present study, we hypothesized that, in human airway smooth muscle (hASM) cells, FCCP-induced mitochondrial depolarization activates the PINK1-Parkin-mediated mitophagy pathway, culminating in the clearance of damaged mitochondria. We observed that exposing hASM cells to 1 µM FCCP for 6 h induced mitochondrial depolarization and a decrease in the volume of intact mitochondria. This mitochondrial depolarization triggered the accumulation of PINK1 in the mitochondria, which mediated phosphorylation of pParkinS65 and an increase in pUbS65 proteins. Confocal imaging of labeled mitochondria and lysosomes demonstrated increased colocalization of mitochondria with lysosomes, and mitophagic flux was confirmed using a pH-sensitive mitochondrial reporter mKeima. Collectively, these findings demonstrate that FCCP robustly activates the canonical PINK1-Parkin mitophagy pathway in hASM cells, providing mechanistic insight into mitochondrial quality control, with potential relevance to airway diseases characterized by mitochondrial dysfunction and altered hASM function.

Keywords:  FCCP; Mitochondrial Quality Control; Mitophagy; PINK1; Parkin

DOI:  https://doi.org/10.1152/ajplung.00050.2026
EMBO J. 2026 Jul 20.

Vps1 drives membrane constriction and fission necessary for endosomal protein sorting.

Shilpa Gopan, Uma Swaminathan, Gurmail Singh, Thomas J Pucadyil.

The trafficking of cargo between endosomes and the Golgi apparatus uses both retromer-dependent and retromer-independent routes. Disruptions to these routes lead to the mis-sorting of lysosomal cargo, and associated metabolic and neurological disorders. The yeast dynamin Vps1 is essential for these trafficking pathways; however, it is not clear whether it directly causes membrane fission. Using cell-free reconstitution and live-cell assays, here we demonstrate that Vps1 assembles into scaffolds on membrane tubules, and uses GTP hydrolysis to force tubule constriction and fission. Vps1 mutants that are unable to assemble or to hydrolyze GTP fail to achieve fission in vitro and cause cargo mis-sorting in vivo. Furthermore, we identify two essential motifs, a lysine-rich phosphoinositide-binding motif and a phenylalanine-rich self-assembly motif, which, when mutated, render Vps1 dysfunctional. Finally, quantitative proteomics revealed a broad range of Golgi and plasma membrane proteins that mis-sort to the vacuole without Vps1. These findings define the Vps1-dependent retrograde pathway's cargo repertoire and confirm Vps1's mechanochemical role in membrane fission.

DOI: https://doi.org/10.1038/s44318-026-00855-4
Stem Cells Transl Med. 2026 07 20. pii: szag042. [Epub ahead of print]15(8):

A human iPSC-derived 3D spinal cord organoid model to study radiation-induced neural injury.

Yifei Jiang, Xubo Li, Jingguang Zeng, Shiju Chen, Runtao Zhou, Yixun Wu, Ganggang Kong, Fawei Liao, Bo Wang, Fangze Qi, Cheng Gu, Shiyi Yin, Qiguang Pang, Weidong Mu, Qingtang Zhu, Canbin Zheng.

   BACKGROUND: Radiation therapy remains a cornerstone in the treatment of primary and metastatic tumors; however, its efficacy is limited by the spinal cord's high sensitivity to radiation-induced injury. To better understand the mechanisms underlying spinal cord radiosensitivity, we developed a three-dimensional human spinal cord organoid model derived from human-induced pluripotent stem cells using a neuroectodermal differentiation protocol that closely mimics embryonic spinal cord development.
METHODS: Mature spinal cord organoids were exposed to a clinically relevant 2 Gy dose of ionizing radiation, and subsequent assessments included evaluation of DNA damage, astrocytic response, and neuronal functionality.
RESULTS: The organoids successfully recapitulated key features of spinal cord development, including neural differentiation, spontaneous electrophysiological activity, and functional maturation. Radiation exposure led to pronounced DNA double-strand breaks, particularly in SOX2-expressing progenitor cells. Astrocyte hyperplasia was evident through increased GFAP expression, indicating a reactive gliosis response. Electrophysiological analysis revealed a marked reduction in spike frequency and burst activity, indicative of impaired neuronal function. Although partial recovery was observed over time, functional deficits persisted, suggesting sustained damage.
CONCLUSION: This human spinal cord organoid model offers a physiologically relevant platform for studying radiation-induced spinal cord injury and provides valuable insights into the cellular and functional consequences of radiation exposure. It holds significant potential for advancing neuroprotective strategies and therapeutic interventions targeting radiation-induced damage in the central nervous system.

Keywords:  DNA damage response; DNA-double strand break; human pluripotent stem cells; radiation-induced damage; spinal cord organoids

DOI:  https://doi.org/10.1093/stcltm/szag042
EMBO J. 2026 Jul 20.

Atg23 prevents aberrant fusion of Atg9 vesicles during delivery to autophagosome formation sites.

Takumi Kimura, Takayuki Shima, Tetsuya Kotani, Hitoshi Nakatogawa.

Autophagosome biogenesis depends on the accurate delivery of membrane lipids to the pre-autophagosomal structure. Golgi/endosome-derived Atg9 vesicles provide the membrane seed for this process, but how they are trafficked through the cytoplasm while avoiding inappropriate fusion remains unclear. Here we show that in Saccharomyces cerevisiae, the soluble Atg9-interacting protein Atg23 remains associated with Atg9 vesicles after their biogenesis. This association shields Atg9 vesicles from aberrant SNARE-dependent fusion as they diffuse through the cytoplasm en route to the autophagosome formation site. We further show that upon vesicle arrival at the site, Atg9 phosphorylation by the autophagy initiation kinase Atg1 releases Atg23, facilitating recruitment of the downstream factor Atg2, a lipid transfer protein for membrane expansion. Together, these findings reveal an Atg1-dependent phosphorylation switch that regulates Atg9 vesicle dynamics during autophagosome biogenesis.

DOI: https://doi.org/10.1038/s44318-026-00867-0