bims-axbals 2026-10-11 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–10–11
twelve papers selected by
TJ Krzystek

Multiple motor proteins regulate TDP-43 anterograde axonal transport.
TDP-43 and ALS - what's wrong with my membranes?
Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.
Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities.
nHOTAIRM1 scaffolds ANXA11-dependent assemblies to drive axonal mRNA localization in human motor neurons.
Integrated electrophysiological and payload-release assessment of neuronal responses to antibody-drug conjugates in human iPSC-derived sensory neurons: implications for in vitro neurotoxicity evaluation.
Dystrophic changes of nigrostriatal axons harboring a SYNJ1 Parkinson's mutation suggest catastrophic failure of endocytic mechanisms.
Herpes simplex virus pUL56 abolishes neuronal activity by removing voltage-gated ion channels from the plasma membrane.
Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy.
Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes.
Increased Expression of α-Synuclein Impairs Trafficking of the Essential SNARE Protein Synaptobrevin-2.
Zbtb18 Deficiency Impairs the Hippocampal Development and Neurite Growth.

Acta Neuropathol. 2026 Oct 09. pii: 47. [Epub ahead of print]152(1):

Multiple motor proteins regulate TDP-43 anterograde axonal transport.

Monica Feole, Victorio M Pozo Devoto, Neda Dragišić, Maria Čarna, Katja Klosterman, Clara Limbaek-Stokin, Giancarlo Forte, Kenneth L Moya, Richard A Smith, Clive N Svendsen, Gorazd B Stokin.

  TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein essential for RNA metabolism. Under physiological conditions, it predominantly resides in the nucleus but is also expressed in the cytoplasm, where it regulates mRNA trafficking and local translation. In nearly 97% of amyotrophic lateral sclerosis (ALS) cases, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation. While its nuclear functions are well characterized, its axonal roles remain poorly understood, despite axonal degeneration being a hallmark of ALS pathology. To address this gap, we investigated TDP-43 localization and transport dynamics in axons of H9-derived human neurons. We compared fluorescently labeled TDP-43 with three well-characterized axonal cargoes, ras-related protein Rab5, synaptophysin, and amyloid precursor protein, and examined protein-protein interactions between TDP-43 and the axonal transport machinery. Our analyses revealed that TDP-43 exhibits active anterograde axonal transport and interacts with multiple kinesin motor proteins, including all three KIF5 isoforms, through the adaptor KLC1, and the synaptic vesicles motor KIF1A. This multi-motor engagement suggests a flexible transport system that ensures mRNA delivery to distal axons. In ALS, where TDP-43 accumulates abnormally in the cytoplasm, this flexibility may become compromised, with multiple transport mechanisms simultaneously affected. This could contribute to progressive accumulation of non-functional TDP-43 granules, disrupting mRNA trafficking and local translation. Our findings provide a foundation for understanding how physiological TDP-43 transport mechanisms may be impaired during disease, highlighting axonal TDP-43 transport pathways as potential therapeutic targets.

Keywords:  Adaptors; Amyotrophic lateral sclerosis; Axonal transport; Cargoes; Motor proteins; TDP-43

DOI:  https://doi.org/10.1007/s00401-026-03071-w
Neurobiol Dis. 2026 Oct 05. pii: S0969-9961(26)00376-1. [Epub ahead of print]230 107630

TDP-43 and ALS - what's wrong with my membranes?

Regina Dahlhaus, Israfil Yalcin, Julia Tischer, Ralf J Braun.

  In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.

Keywords:  Amyotrophic lateral sclerosis; Frontotemporal dementia; LATE; TDP-43 proteinopathy

DOI:  https://doi.org/10.1016/j.nbd.2026.107630
Nat Neurosci. 2026 Oct 07.

Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.

Maria Stavrou, Áine Bríd Heffernan, Roderick N Carter, Owen Dando, Zoeb Jiwaji, Karen Burr, Jyoti Nanda, David Villarroel-Campos, Alya Masoud Abdelhafid, Justyna Cholewa-Waclaw, Daniel Soong, David Story, Giampietro Schiavo, Giles E Hardingham, Siddharthan Chandran, Bhuvaneish T Selvaraj.

Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked-human-induced pluripotent stem-cell-derived astrocytes carrying the C9ORF72 mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.

DOI: https://doi.org/10.1038/s41593-026-02464-0
J Huntingtons Dis. 2026 Oct 09. 18796397261494078

Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities.

Florence Dm Wavreil, Sabine Schipper-Krom, Eric Aj Reits.

  Huntington's Disease (HD) is a progressive neurodegenerative disease that is caused by a CAG-repeat expansion in the exon 1 of the huntingtin (HTT) gene, which results in the formation of toxic mutant HTT (mHTT) exon 1 fragments with expanded polyglutamine (polyQ) stretch. These mHTT fragments are prone to misfolding and aggregation, causing cytotoxicity, particularly in the striatal neurons. The lack of disease-modifying treatments for HD emphasizes the need to develop new therapeutic strategies to prevent or reverse HD pathology. The reduction of the mHTT exon 1 fragment by facilitating its selective degradation may be a promising approach to prevent aggregation, thereby delaying or preventing the onset of HD. Since the ubiquitin-proteasome system (UPS) is not impaired in HD, enabling strategies to selectively target mHTT towards the UPS or autophagy would improve mHTT clearance. In this review, we describe three main strategies to modulate mHTT levels. First, we discuss different ubiquitin-modifying enzymes that have been associated with HTT and may act as possible therapeutic targets. Next, we focus on more targeted approaches for the selective degradation of mHTT with engineered small molecule compounds such as PROTACs and AUTOTACs. Finally, we summarize the current knowledge of HTT-specific intracellular antibodies (intrabodies) as potential candidates for gene therapy. Together, this review aims to assess different possible avenues for the treatment of HD.

Keywords:  autophagy; huntingtin; intrabodies; proteasome; proteostasis; small molecule compounds

DOI:  https://doi.org/10.1177/18796397261494078
Cell Death Differ. 2026 Oct 05.

nHOTAIRM1 scaffolds ANXA11-dependent assemblies to drive axonal mRNA localization in human motor neurons.

Paolo Tollis, Tiziana Santini, Adriano Setti, Walter Visciglio, Jessica Rea, Davide Mariani, Alessandro Belvedere, Monica Ballarino, Irene Bozzoni, Pietro Laneve.

Long noncoding RNAs (lncRNAs) are well recognized as regulators of neuronal development and function, yet their integration into canonical axonal transport pathways, an essential component of spatial gene regulation in highly polarized cells, remains incompletely defined. It is still unclear to what extent individual lncRNAs confer cargo selectivity and couple discrete mRNA cohorts to established transport machineries. Here we identify a cytoplasmic role for the neuronal isoform of the lncRNA HOTAIRM1 (nHOTAIRM1) in shaping the axonal RNA landscape of human induced pluripotent stem cell -derived spinal motor neurons (spMNs). We show that nHOTAIRM1 associates with Annexin A11 (ANXA11), a factor linked to lysosome-coupled movement of RNA granules, and engages a defined subset of motor neuron-relevant mRNAs. Transcriptome-wide and targeted interaction assays, together with computational mapping and steric competition, support direct RNA-RNA pairing between nHOTAIRM1 and mRNAs involved in cytoskeletal organization and synaptic or vesicular functions, while spatial analyses place these RNA pairs in close proximity within the soma and neurites. Loss-of-function experiments further show that nHOTAIRM1 depletion reduces the association of these mRNAs with ANXA11-positive complexes and diminishes their enrichment in neuronal projections, an effect that is recapitulated by ANXA11 depletion. Collectively, these findings support a model in which nHOTAIRM1 contributes to the selective recruitment of cargo mRNAs into ANXA11-associated transport assemblies, thereby promoting their localization within distal neurites. More broadly, our findings provide mechanistic insight into how a lncRNA can regulate mRNA sorting, and compartment-specific RNA trafficking in human spMNs.

DOI: https://doi.org/10.1038/s41418-026-01880-w
Front Toxicol. 2026 ;8 1855330

Integrated electrophysiological and payload-release assessment of neuronal responses to antibody-drug conjugates in human iPSC-derived sensory neurons: implications for in vitro neurotoxicity evaluation.

Taeko Kuroda, Xiaobo Han, Toshiki Mochizuki, Yuto Ishibashi, Aya Goto, Yuki Seki, Norimasa Miyamoto, Takashi Yoshinaga, Shoji Asakura, Ikuro Suzuki.

  Antibody-drug conjugates (ADCs) enable tumor-specific drug delivery; however, target antigen-independent adverse events, including peripheral neuropathy, remain a significant clinical concern. The mechanisms underlying ADC-induced neurotoxicity, particularly the relationship between payload release and alterations in neuronal function, are not yet fully understood. In this study, we established an analytical platform that integrates microelectrode array (MEA) recordings using human induced pluripotent stem cell (iPSC)-derived sensory neurons with quantitative measurement of payload levels detected after ADC exposure under culture conditions, enabling functional evaluation of the direct effects of ADCs and their payloads on neuronal activity. The microtubule inhibitors monomethyl auristatin E (MMAE) and Lys-SMCC-DM1, when administered as free payloads, suppressed neuronal activity, as indicated by reduced firing rates, decreased spike amplitudes, together with neurite fragmentation. In contrast, their corresponding ADCs, brentuximab vedotin and trastuzumab emtansine, showed limited detectable effects on neuronal activity under the present experimental conditions. Conversely, the topoisomerase I inhibitor SN-38 enhanced neuronal activity, as evidenced by increased firing rates and spike amplitudes without marked morphological disruption. Similar functional changes were observed with sacituzumab govitecan. Furthermore, quantitative analysis revealed substantially higher measured payload levels at the 168-h endpoint following sacituzumab govitecan exposure than following brentuximab vedotin or trastuzumab emtansine exposure under the present experimental conditions. These findings suggest that the neuronal functional responses observed following ADC exposure may be associated with differences in measured payload levels and are consistent with the possibility of target antigen-independent effects. The integrated platform developed in this study enables quantitative assessment of neuronal functional responses to ADCs and payloads and may serve as a complementary tool for in vitro neurotoxicity evaluation during ADC design and development.

Keywords:  antibody-drug conjugates; human iPSC-derived sensory neurons; microelectrode array; neurotoxicity; payload release; peripheral neuropathy

DOI:  https://doi.org/10.3389/ftox.2026.1855330
Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2622215123

Dystrophic changes of nigrostriatal axons harboring a SYNJ1 Parkinson's mutation suggest catastrophic failure of endocytic mechanisms.

Yumei Wu, Peng Xu, James Moran, C Shan Xu, Kenneth J Hayworth, Mian Cao, Lin Shao, D James Surmeier, Harald F Hess, Pietro De Camilli.

  Synaptojanin 1 is a brain enriched phosphoinositide phosphatase implicated in endocytosis at the synapse. A mutation (R258Q) that selectively impairs its Sac1 phosphatase domain causes early onset familial Parkinsonism. Neurons of mice with this mutation display synaptic vesicle traffic defects across the brain, but selective dystrophic changes in a subset of dopaminergic axons in the dorsolateral striatum. Using correlative light microscopy-FIB-SEM of mutant mouse striata to visualize in 3D these abnormal structures we show that they represent clusters of focal axonal dilations harboring massive, onion-like DAT enriched plasma membrane infoldings, generally localized next to cell bodies of neighboring cells, often engulfing evaginations of such cells. This dysmorphia was associated with a deficit in dopamine release in the same striatal region. Given the involvement of Synj1 in endocytic mechanisms, these structures may reflect an imbalance between exocytosis and endocytosis. Their occurrence only in a subset of axons suggests a vulnerability threshold of these axons beyond which the expansion of the plasma membrane is not counteracted by compensatory mechanisms.

Keywords:  Parkinson’s disease; auxilin; dopamine transporter; endocytic recycling; synaptojanin

DOI:  https://doi.org/10.1073/pnas.2622215123
Sci Adv. 2026 Oct 09. 12(41): eaei1796

Herpes simplex virus pUL56 abolishes neuronal activity by removing voltage-gated ion channels from the plasma membrane.

Daniel A Nash, Henry G Barrow, P Robin Antrobus, Alex S Nicholson, John Suberu, Harvey E Johnston, Martin Potts, Marta A Almeida, Valeria Lulla, Colin M Crump, Anton J Enright, Michael P Weekes, Janet E Deane, Stephen C Graham.

Herpes simplex virus 1 (HSV-1) infections of the central nervous system cause encephalitis and are associated with increased risk of neurodegeneration, yet the molecular consequences of lytic infection in human neurons remain incompletely defined. We map the transcriptomic, proteomic, and surface-proteome changes induced by HSV-1 across the lytic infection cycle in human induced pluripotent stem cell-derived cortical glutamatergic neurons. HSV-1 drives extensive plasma-membrane remodeling, including the removal of voltage-gated sodium, potassium, and calcium channels, resulting in a profound loss of synchronous calcium signaling. We identify the viral ubiquitin-ligase adaptor pUL56 as the principal effector of this process: pUL56-dependent degradation of ion channels abolishes coordinated calcium signaling, whereas mutation of its E3-ligase-binding motifs preserves synchrony. Furthermore, expression of pUL56 alone is sufficient to abolish neuronal electrical activity. These findings establish pUL56 as a potent viral suppressor of neuronal excitability.

DOI: https://doi.org/10.1126/sciadv.aei1796
bioRxiv. 2026 Aug 10. pii: 2026.08.07.743589. [Epub ahead of print]

Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy.

Minghao Chen, Aniketh Bishnu, Yongjia Duan, Julia F Riley, Qingyang Ni, Aaron Joiner, Isaac J Allen, Erika L F Holzbaur, Ian G Ganley, James H Hurley.

Rubicon is a negative regulator of autophagy and the endolysosomal network (ELN) and an antagonist of the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). Inhibition of Rubicon is considered a potential means to therapeutically upregulate autophagy and the ELN to treat Parkinson's disease and other conditions characterized by autophagic and ELN dysfunction. Rubicon is specific for the UVRAG-containing PI3KC3-C2 over the purely autophagic ATG14- containing PI3KC3-C1 complex. Here, we determined the high-resolution cryo-electron microscopy structure of PI3KC3-C2 in complex with the PI3KC3-binding domain (PIKBD) of Rubicon and compared it to cryo-EM structures of unbound PI3KC3-C2 and PI3KC3-C1. Rubicon binds directly to PI3KC3-C2 only via the BARA domain of the BECN1 subunit, which is common to both C1 and C2. The selectivity of Rubicon for the PI3KC3-C2 complex over the PI3KC3-C1 complex is attributed to a conformation of the BECN1 BARA domain induced by UVRAG, rather than to direct contact with UVRAG or direct antagonism by the ATG14 subunit of PI3KC3-C1. Targeted disruption of the Rubicon:PI3K3-C2 structural interface by site-directed mutations enhances mitophagic activity in human epithelial cells to levels comparable to those observed in Rubicon knockout (KO) cells. Similarly, disruption of the interaction in Rubicon-overexpressing hippocampal neurons restored lysosomal flux to wild-type levels. These data show that suppressing the function of PI3K3- C2 can fully account for the negative regulatory effects of Rubicon in the autophagy and ELN pathways.
Significance Statement: Endolysosome maturation and autophagosome-lysosome fusion require the production of phosphatidylinositol 3-phosphate (PI(3)P) by the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). Rubicon is a key negative regulator of endolysosomes and autophagy that suppresses PI3KC3-C2 activity. Here, we reveal in atomistic detail how Rubicon selectively recognizes PI3KC3-C2. Disrupting the Rubicon-PI3KC3-C2 interaction restores mitophagy and enhances lysosomal activity to the same extent as Rubicon gene deletion, establishing that PI3KC3-C2 inhibition fully accounts for the biological regulatory effects of Rubicon in the autophagy and lysosome pathways.

DOI: https://doi.org/10.64898/2026.08.07.743589
Nat Commun. 2026 09 03. pii: 10512. [Epub ahead of print]17(1):

Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes.

Dávid Hargitai, Márton Molnár, András Rubics, Iván Bodor, Dóra Baukál, Anikó Nagy, Virág Balogh, Zsófia Simon-Vecsei, Gábor Juhász, Péter Lőrincz.

Endosomal maturation determines whether internalized cargo is recycled or degraded, yet the logic governing early endosomal fusion remains incompletely defined. Although commonly depicted as a linear Rab5-to-Rab7 transition mediated by a single SNARE pathway, we show that early endosome maturation is driven by multiple parallel, non-interchangeable SNARE complexes. Using Drosophila nephrocytes as a tractable in vivo model, we define a Syx12L-Snap29-Ykt6 complex that mediates homotypic early endosomal fusion and identify two related assemblies-Syx7L-Snap29-Ykt6 and Syx7L-Snap29-Vamp7-that promote later endosomal and lysosomal fusion with distinct Rab requirements. When the canonical Syx12L pathway is disrupted, alternative complexes remain active and generate aberrant endolysosomal swirls which also form in the absence of Rab5 or early endosomal tethers. Thus, Rab5-independent membrane progression toward lysosomes persists but is insufficient to produce fully functional degradative organelles. Together, our findings reveal a network of parallel fusion pathways underlying endosome maturation.

DOI: https://doi.org/10.1038/s41467-026-77479-z
J Neurochem. 2026 Oct;170(10): e70568

Increased Expression of α-Synuclein Impairs Trafficking of the Essential SNARE Protein Synaptobrevin-2.

Elyas H Arvell, James P Carroll, Joshua Saito, Holly Melland, Ranjith R Unnithan, Chris French, Danny M Hatters, Sarah L Gordon.

  α-Synuclein is a presynaptic protein that has been extensively studied for its role in Parkinson's disease. Multiplication and missense variants in the gene encoding α-synuclein are causes of familial PD, and aggregated α-synuclein is a major component of Lewy bodies and Lewy neurites, the histopathological hallmark of the disease. However, the native function of α-synuclein remains unclear, though several lines of evidence suggest it modulates presynaptic function. α-Synuclein binds the vesicular SNARE protein synaptobrevin-2/VAMP2, and increased levels of α-synuclein potentiate SNARE complex levels without impacting exocytic rate. Given the essential role of synaptobrevin-2 in synaptic function we sought to examine how increased expression of α-synuclein, at levels observed in familial synucleinopathies with SNCA triplication, impacts the trafficking of this essential SNARE protein. Modest (approximately 2-fold) overexpression of α-synuclein in cultured murine hippocampal neurons caused a slowing in the endocytic retrieval of synaptobrevin-2, without impacting either the targeting of the protein to synapses or altering endocytosis. We also show that α-synuclein is not working antagonistically with the synaptobrevin-2 chaperone synaptophysin, and likely acts at least partially via direct binding to synaptobrevin-2. Finally, increased expression of α-synuclein induces synaptic depression upon repeated neuronal depolarisation, in a manner requiring binding to synaptobrevin-2. We reveal α-synuclein as a modulator of synaptobrevin-2 endocytic trafficking and highlight perturbed SNARE protein trafficking as a potential contributor to synaptic dysfunction and neuronal health in Parkinson's disease.

Keywords:  Parkinson's disease; endocytosis; neurotransmission; protein trafficking; synaptobrevin‐2; α‐synuclein

DOI:  https://doi.org/10.1111/jnc.70568
Mol Neurobiol. 2026 Oct 08. pii: 957. [Epub ahead of print]63(1):

Zbtb18 Deficiency Impairs the Hippocampal Development and Neurite Growth.

Yuzhuo Zhou, Yiyuli Tang, Cheng Peng.

  Previous studies of the transcription factor Zbtb18 have primarily focused on its role in cortical development, whereas its function during hippocampal development remains poorly understood. In this study, we investigated the role of Zbtb18 in mouse hippocampal development using histological, transcriptomic, and functional approaches. Immunostaining demonstrated that Zbtb18 was partially overlapped with the neural progenitor marker Pax6, intermediate progenitor marker Tbr2, postmitotic neuronal marker Tbr1, and neuronal marker NeuN in the hippocampal primordium from embryonic day 13.5. Loss of Zbtb18 was associated with pronounced hippocampal malformations, including Dentate Gyrus disorganization and altered cellular architecture. Single-nucleus RNA sequencing at embryonic day 18.5 suggested alterations in neuronal composition within the Cornu Ammonis and Dentate Gyrus regions, accompanied by increased Prox1 expression and abnormal progenitor cell proliferation. Pathway analyses identified transcriptional alterations associated with neurogenesis, neuronal differentiation, neuronal morphogenesis, and cAMP signaling. Consistent with these findings, primary hippocampal neurons derived from Zbtb18-deficient embryos exhibited reduced longest neurite length and total neurite length in vitro. Pharmacological activation of cAMP signaling with forskolin partially improved neurite growth in Zbtb18-deficient neurons. Together, these findings suggest that Zbtb18 regulates hippocampal development and neurite growth, in which the cAMP signaling pathway is involved in the neuronal morphological defect.

Keywords:   Zbtb18 ; CAMP signaling; Hippocampus; Neurite growth; SnRNA-Seq

DOI:  https://doi.org/10.1007/s12035-026-06254-4