bims-axbals 2026-01-18 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–01–18
thirteen papers selected by
TJ Krzystek

Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.
Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.
LAMP1 and LAMP2A localise to axonal organelles with distinct motility dynamics and partially overlapping molecular signatures in human neurons.
A guide to selecting high-performing antibodies for GCase (UniProt ID: P04062) for use in western blot, immunoprecipitation, and immunofluorescence.
Compartment-specific transcriptome of motorneurons reveals impaired extracellular matrix signaling and activated cell cycle kinase in FUS-ALS.
Reticulon-1 synthesis controls outgrowth and microtubule dynamics in injured cortical axons.
A general one-step protocol to generate impermeable fluorescent HaloTag substrates for in situ live cell application and super-resolution imaging.
Caspr1 silencing promotes axon regeneration in both peripheral and central nervous systems via negative regulation of neurofascin.
Nanoscale Imaging of Neurons Under Near-Physiological Conditions Using Field-Emission Scanning Electron Microscopy.
PLGA Nanoparticles Restore Acidic pH and Degradative Function to Compromised Lysosomes with Cy3-Labeling Providing Enhanced Tracking to Lysosomes.
SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.
CHAMP1 is an essential regulator for human myoblast fusion and muscle development.
MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes.

Mol Neurobiol. 2026 Jan 17. 63(1): 370

Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.

Matthew Anthony White, Leon Crowley, Francesca Massenzio, Xingli Li, Michael Niblock, Sara Milani, Michael Philip Coleman, Sami J Barmada, Jemeen Sreedharan.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by TAR DNA-binding protein 43 kDa (TDP-43) pathology. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. We show that TDP-43 activates GSK3 and promotes caspase-dependent cleavage of TDP-43, generating C-terminal fragments. We determine the functional importance of the N-terminal Asp89 caspase cleavage site in regulating TDP-43 proteostasis in both wild-type and ALS-linked TDP-43 variants and show that GSK3 inhibition selectively reduces truncated TDP-43 species, lowers nuclear TDP-43 levels, and improves neuronal survival. Neuroprotective effects were conserved in primary rodent cortical neurons, primary mouse motor neurons, and human iPSC-derived cortical neurons, highlighting the potentially broad therapeutic potential of GSK3 inhibition. We also find that the GSK3 inhibitor CHIR99021 reduces GSK3 RNA and protein expression and increases GSK3 phosphorylation, indicating novel mechanisms by which it acts to inhibit GSK3 activity. Unexpectedly, an N-terminally truncated variant (TDP-43N-Del), originally designed as a negative transfection control, exerted modest toxicity, potentially through retained susceptibility to caspase cleavage. Together, our findings uncover a caspase-mediated mechanism linking GSK3 activity to TDP-43 turnover, localisation, and neurotoxicity, and position GSK3 inhibition as a promising strategy to mitigate TDP-43-driven neurodegeneration in ALS-FTD.

Keywords:  ALS-FTD; Caspase-dependent cleavage; GSK3 inhibition; Kinase inhibition; Neurodegeneration; Neurotoxicity attenuation; TDP-43; TDP-43 C-terminal fragments

DOI:  https://doi.org/10.1007/s12035-026-05675-5
BMB Rep. 2026 Jan 12. pii: 6696. [Epub ahead of print]

Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.

Hyun-Ji Ham, Jin-A Lee.

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.
J Cell Sci. 2026 Jan 15. pii: jcs.264466. [Epub ahead of print]

LAMP1 and LAMP2A localise to axonal organelles with distinct motility dynamics and partially overlapping molecular signatures in human neurons.

Reem Abouward, Alya Masoud Abdelhafid, Oscar G Wilkins, Song-Yi Lee, Fairouz Ibrahim, Mark Skehel, Alice Ting, Nicol Birsa, Jernej Ule, Giampietro Schiavo.

  LAMP1 and LAMP2A are abundant proteins of late endosomal/lysosomal compartments that are often used interchangeably to label what is assumed to be the same organelle population, potentially obscuring distinct physiological roles. Here, we characterised the axonal transport dynamics of LAMP1- and LAMP2A-positive compartments in human iPSC-derived cortical neurons. We found that LAMP1-positive organelles move slower in the retrograde direction, pause more frequently, and display a broader anterograde velocity distribution than LAMP2A-positive vesicles, indicating distinct trafficking behaviours. Co-transport analysis revealed that approximately 65% of motile LAMP-positive organelles carry both markers, with higher co-transport in the retrograde direction. To explore molecular differences underlying these behaviours, we performed proximity labelling using full-length LAMP1 or LAMP2A fused to the light-activated biotin ligase, LOV-Turbo. This approach revealed largely overlapping interactomes, with LAMP2A-associated proteins forming a subset of the LAMP1 interactome and showing an enrichment for synaptic vesicle-related proteins. We further validated ZFYVE16 as a novel interactor of both compartments. Together, our findings indicate that LAMP1- and LAMP2A- positive organelles share overlapping molecular identities but represent functionally distinct axonal populations with divergent transport dynamics.

Keywords:  Axonal transport; Endosomes; Lysosomes; Proximity labelling; Synaptic vesicles

DOI:  https://doi.org/10.1242/jcs.264466
F1000Res. 2025 ;14 1400

A guide to selecting high-performing antibodies for GCase (UniProt ID: P04062) for use in western blot, immunoprecipitation, and immunofluorescence.

Donovan Worrall, Charles Alende, Maryam Fothouhi, Vera Ruíz Moleón, Sara González Bolívar, Riham Ayoubi, Vincent Francis, Carl Laflamme, Peter S McPherson.

  The human GBA1 gene encodes glucocerebrosidase (GCase), a lysosomal enzyme that hydrolyzes glucosylceramides. Variants in GBA1 and reduced GCase activity have been linked to Parkinson's disease and Gaucher's disease. Here we have characterized twenty-four GCase commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While the use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Keywords:  GBA1; GCase; P04062; antibody characterization; antibody validation; immunofluorescence; immunoprecipitation; western blot

DOI:  https://doi.org/10.12688/f1000research.174230.1
Neurobiol Dis. 2026 Jan 10. pii: S0969-9961(26)00012-4. [Epub ahead of print] 107268

Compartment-specific transcriptome of motorneurons reveals impaired extracellular matrix signaling and activated cell cycle kinase in FUS-ALS.

Vitaly Zimyanin, Banaja P Dash, Theresa Simolka, Hannes Glaß, Arun Pal, Felix Haidle, Kathi Zarnack, Riya Verma, Vivek Khatri, Christopher Deppmann, Eli Zunder, Michaela Müller-McNicoll, Stefanie Redemann, Andreas Hermann.

  Mutations in FUSED IN SARCOMA (FUS) cause juvenile-onset amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS-ALS involves impaired transcription and splicing, DNA damage response, and axonal degeneration. However, the molecular pathophysiology and the link between somatic and axonal phenotypes are still poorly understood. We evaluated whether compartment-specific transcriptome differences could distinguish and drive early axonal degeneration. We used iPSC-derived motor neurons (MNs) coupled with microfluidic approaches to generate RNA-sequencing profiles from axonal and somatodendritic compartments. We demonstrate that the axonal transcriptome is unique and distinct, with RNA metabolism, extracellular secretion, and matrix disassembly pathways particularly enriched in distal axonal compartments. FUS mutation leads to changes in distinct pathways that were clustered in only a few distinct protein-protein interaction (PPI) networks. Somatodendritic changes upon FUS mutation include WNT signaling, mitochondrial, extracellular matrix (ECM)-, and synapse-related functions. In contrast, analysis of the axonal transcriptome in mutant MNs centers on the PLK1 pathway, mitochondrial gene expression, and regulation of inflammation. Comparison to CLIP-seq data revealed a significant enrichment for PLK1 and DNA replication pathways in axons. PLK1 upregulation did not activate cell-cycle re-entry but contributed to mutant MN survival, and its inhibition increased neuronal cell death. We propose that upregulation of PLK1 represents an early event in the pathogenesis of ALS and could act in response to DNA damage, mitochondrial damage, and immune response activation in the affected cells. Additionally, downregulation of ECM pathways in the somatodendritic compartment and axons could explain strongly compromised dynamics of axonal outgrowth. Overall, we provide a novel valuable resource of the potential targets and affected processes changed in the specific compartments of FUS-ALS motoneurons.

Keywords:  Amyotrophic lateral sclerosis; Axon degeneration; Axonal outgrowth; Axonal transcriptome; Cell cycle; DNA damage, PLK1; ECM; Induced pluripotent stem cells; RNA sequencing

DOI:  https://doi.org/10.1016/j.nbd.2026.107268
Life Sci Alliance. 2026 Apr;pii: e202503571. [Epub ahead of print]9(4):

Reticulon-1 synthesis controls outgrowth and microtubule dynamics in injured cortical axons.

Alejandro Luarte, Javiera Gallardo, Daniela Corvalán, Ankush Chakraborty, Cláudio Gouveia Roque, Francisca Bertin, Carlos Contreras, Juan Pablo Ramírez, André Weber, Waldo Acevedo, Werner Zuschratter, Rodrigo Herrera-Molina, Úrsula Wyneken, Andrea Paula-Lima, Tatiana Adasme-Rocha, Jorge Toledo, Rodrigo Vergara, Antonia Figueroa, Carolina González, Christian González-Billault, Ulrich Hengst, Andrés Couve.

The regenerative potential of developing cortical axons depends on intrinsic mechanisms, such as axon-autonomous protein synthesis, that are still not fully understood. An emerging factor in this regenerative response is the bidirectional interplay between microtubule dynamics and the axonal ER. We hypothesize that locally synthesized ER proteins regulate microtubule dynamics and the regeneration of cortical axons. RNA data mining identified the ER-shaping protein Reticulon-1 as a relevant candidate across eight axonal transcriptomes. Using microfluidics, we show that axonal treatment with a small RNA against Reticulon-1 mRNA (Reticulon-1 knockdown) increases outgrowth of injured cortical axons while reducing their tubulin levels. We show by live-cell imaging that axonal Reticulon-1 knockdown increases microtubule growth rate in noninjured axons and restores this parameter after injury. Axonal inhibition of the microtubule-severing protein Spastin prevents the effects of Reticulon-1 knockdown over tubulin levels and outgrowth. We provide evidence that the Reticulon-1C isoform is synthesized within axons and attenuates Spastin-mediated microtubule severing. These findings support a model in which axonal protein synthesis regulates microtubule dynamics and axon outgrowth after injury.

DOI: https://doi.org/10.26508/lsa.202503571
Nat Commun. 2026 Jan 12. 17(1): 426

A general one-step protocol to generate impermeable fluorescent HaloTag substrates for in situ live cell application and super-resolution imaging.

Kilian Roßmann, Ulrich Pabst, Bianca C Baciu, Siqi Sun, Christiane Huhn, Christina Holmboe Olesen, Maria Kowald, Eleni Tapp, Marie Bieck, Ramona Birke, Brenda C Shields, Pyeonghwa Jeong, Jiyong Hong, Michael R Tadross, Joshua Levitz, Martin Lehmann, Noa Lipstein, Johannes Broichhagen.

Visualization of proteins can be achieved by genetically grafting HaloTag Protein (HTP) into the protein of interest followed by incubation with a dye-linked HaloTag Ligand (HTL). This approach allows for use of fluorophores optimized for specific optical techniques or of cell-impermeable dyes to selectively label cell surface proteins. However, these two goals often conflict, as many high-performing dyes exhibit membrane permeability. Here we show that several dye-HTL reagents can be made cell-impermeable by inserting a charged sulfonate directly into the HTL, leaving the dye moiety unperturbed, using a one-step protocol. We validate such compounds, termed dye-SHTL (dye shuttle), in living cells, and demonstrate exclusive membrane staining. In transduced primary hippocampal neurons, we label a neuromodulatory receptor with dyes optimized for stimulated emission by depletion super-resolution microscopy, allowing accuracy in distinguishing surface versus internal receptors of the presynaptic terminal. This approach offers broad utility for surface-specific protein labelling.

DOI: https://doi.org/10.1038/s41467-025-68134-0
Biochem Biophys Res Commun. 2025 Dec 31. pii: S0006-291X(25)01914-X. [Epub ahead of print]799 153198

Caspr1 silencing promotes axon regeneration in both peripheral and central nervous systems via negative regulation of neurofascin.

Yan-Xia Ma, Shan-Wen Wei, Hao-Nan Zhang, Ming-Ming Zou, Saijilafu.

  The regenerative capacity of the adult mammalian central nervous system is severely limited, posing a significant challenge for functional recovery after injury. To explore novel approaches to support neuronal regeneration, this study examined the role of Caspr1 as an inhibitor of axonal regeneration. Caspr1 expression was downregulated in dorsal root ganglion neurons in a rodent model of nerve injury and absent from regenerating axons, but localized to the neuronal soma membrane. Functional assays revealed that knocking down Caspr1 in cultured central and peripheral neurons using targeted siRNA significantly enhanced axon growth. Silencing Caspr1 in sensory neurons and retinal ganglion cells promoted the regeneration of sensory axons and the optic nerve, respectively. We further identified Nfasc as a key downstream mediator, and that Nfasc expression was negatively regulated by Caspr1. Taken together, these findings identify Caspr1 as a potent negative regulator of axonal regeneration and the novel Caspr1-Nfasc pathway as a promising therapeutic target for the axonal regeneration of mature neurons following injury.

Keywords:  Axon regeneration; Axotomy; Caspr1; Dorsal root ganglion neurons; Nfasc; Retinal ganglion cells

DOI:  https://doi.org/10.1016/j.bbrc.2025.153198
Microsc Res Tech. 2026 Jan 14.

Nanoscale Imaging of Neurons Under Near-Physiological Conditions Using Field-Emission Scanning Electron Microscopy.

Yuri Yamada, Takaaki Hatanaka, Minoru Hirano.

  Visualization of neuronal ultrastructure facilitates molecular and biochemical analyses that may help to better elucidate neural function and information processing. While the neuron exists at the micron scale, critical events such as synaptic vesicle release and dendritic spine remodeling occur at the nanometer scale, necessitating submicron resolution. Scanning electron microscopy (SEM) provides high-resolution imaging at these scales. However, the commonly used dehydration-based sample preparation method induces morphological distortions, while environmental SEM requires specialized equipment that is costly and difficult to operate. The NanoSuit method has recently emerged as a promising alternative, enabling SEM observations under high-vacuum conditions without standard (dehydration-based) pretreatment. Although known to be successful when applied to specimens with protective surface layers such as insects, flowers, and wet tissues, its effectiveness when examining "bare" cultured cells has not been thoroughly explored. Here, we present a modified NanoSuit protocol for SEM examination of cultured neurons and compare it with standard pretreatment. We demonstrate that traditional methods frequently cause neuronal transection and loss of fine dendritic processes, particularly during early development of neurons. However, the modified NanoSuit approach preserves neuronal morphology, enabling clear visualization of thin neurites and their interactions. Further, we successfully implemented correlative light and electron microscopy (CLEM) using this method, enabling the colocalization of cytoskeletal proteins such as actin and tubulin with the surface features observed by SEM. This combination of morphological preservation and molecular localization provides a more accurate and holistic understanding of neuronal structures, benefiting studies on neural development, synaptic connectivity, and related biomedical applications.

Keywords:  NanoSuit; field‐emission scanning electron microscopy; nanoscale analysis; neurons; wet biological specimens

DOI:  https://doi.org/10.1002/jemt.70103
Am J Physiol Cell Physiol. 2026 Jan 14.

PLGA Nanoparticles Restore Acidic pH and Degradative Function to Compromised Lysosomes with Cy3-Labeling Providing Enhanced Tracking to Lysosomes.

Jiaqi Li, Tianchen Wang, Wennan Lu, Davit Jishkariani, Andrew Tsourkas, Simon Kaja, Kyle H Vining, Jedtanut Thussananutiyakul, Ashley Spence, Rohini M Nair, Joshua L Dunaief, Claire H Mitchell.

  Lysosomal dysfunction and elevated lysosomal pH are hallmark features of age-related neurodegenerative diseases including Age-related Macular Degeneration (AMD), Alzheimer's Disease (AD), and Parkinson's Disease (PD). Restoring lysosomal acidity is important for maintaining enzymatic degradation, preventing protein aggregation, and reducing cellular waste accumulation in degenerating tissues. Acidic nanoparticles represent a promising therapeutic strategy to normalize lysosomal pH; however, accurate monitoring of their delivery, retention, and dosage is critical for rigorous evaluation. To address this, we developed fluorescently labeled poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles conjugated with Cyanine3 amine (Cy3). Nanoparticle uptake was systematically optimized, achieving over 90% delivery to lysosomes of induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells. Uptake rates varied among adjacent cells. Once internalized, nanoparticles demonstrated remarkable stability, with no detectable change in concentration, distribution, or size for at least 28 days. iPS-RPE cells exhibited higher nanoparticle internalization compared to the ARPE-19 cell line and optic nerve head astrocytes. The capacity of the nanoparticles to restore function to stressed lysosomes was confirmed by their ability to reacidify lysosomes, restore cathepsin B activity and increase levels of active cathepsin D. The nanoparticles also reduced levels of LC3II in astrocytes treated with chloroquine, indicating they can also restore autophagy rates. In summary, this study demonstrates the value of Cy3 labeling for enhanced nanoparticle tracking to lysosomes. The findings also identify PLGA nanoparticles as powerful tools for restoring degradative lysosomal function and autophagy in cells undergoing lysosomal stress.

Keywords:  Lysosomal pH; age dependent neurodegenerations; autophagy; nanoparticle trafficking; retina

DOI:  https://doi.org/10.1152/ajpcell.00494.2025
Cell Commun Signal. 2026 Jan 15.

SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.

Cristina Trujillo-Del Río, Seda Koyuncu, Julia Tortajada-Pérez, Mar Collado-Pérez, Ana Pilar Gómez-Escribano, Carlos Mora, Christian Neri, Agustín Lahoz, Marta Roca, José María Millán, Yolanda Sanz, David Vilchez, Andrea Del Valle Carranza, Rafael P Vázquez-Manrique.

Huntington's disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene resulting in an extended polyglutamine (polyQ) stretch in the protein, which is prone to aggregation and toxicity. In addition to a proteostasis imbalance, growing evidence highlights the role of mitochondrial dysfunction in HD progression. Here we explore the role of SIR-2.3/SIRT4, a mitochondrial sirtuin, in polyQ-expanded peptides and mutant huntingtin (mHTT) toxicity using C. elegans and mammalian models. Notably, loss of sir-2.3 function results in neuronal protection mediated by AMPK activation and enhanced autophagy. These neuroprotective effects require the transcription factors DAF-16/FOXO and NHR-49, which regulate autophagy and metabolism. To explore the translational potential of these findings, we used soft ATP synthase inhibitors to mimic sir-2.3 ablation, successfully reducing mHTT-induced neuronal toxicity. These results identify the SIRT4-AMPK axis as a critical regulator linking mitochondrial metabolism, autophagy, and neuronal homeostasis in HD. These findings not only advance our understanding of HD pathogenesis but also offer promising therapeutic targets for restoring proteostasis and neuronal resilience capacity against neurodegenerative diseases.

DOI: https://doi.org/10.1186/s12964-026-02655-z
Nat Commun. 2026 Jan 15. 17(1): 546

CHAMP1 is an essential regulator for human myoblast fusion and muscle development.

Haifeng Zhang, Min Zhou, Zheng Zhang, Zhaoning Wang, Ruifeng Shi, Yushu Wang, Xiaolin Wei, Renjie Shang, Jianwen Li, Cuiyu He, Jin Xie, Yarui Diao, Pengpeng Bi.

Human skeletal muscle comprises myofibers formed by fusion of thousands of myoblasts. This process depends on tightly regulated, muscle-specific fusogens, but its genetic control remains poorly understood. Here, we identify CHAMP1 (Chromosome Alignment Maintaining Phosphoprotein 1) as essential for human myoblast fusion in vitro and in vivo. Genomic and protein-interaction assays reveal a noncanonical role for CHAMP1 as a MyoD cofactor that directly activates expression of the key muscle fusogen Myomaker. As established in prior clinical reports, CHAMP1 mutations in patients cause developmental delay, hypotonia, and muscle weakness. Consistently, patient-derived cells show fusion defects that can be fully rescued by restoring Myomaker expression. Structure and function analyses identify C2H2-type zinc-finger motifs on CHAMP1 protein that are both necessary and sufficient for MyoD interaction and Myomaker expression. These findings highlight a cell-autonomous role for CHAMP1 in muscle development and disease and point to therapeutic avenues for treating CHAMP1-related muscle development defects.

DOI: https://doi.org/10.1038/s41467-025-67584-w
EMBO J. 2026 Jan 15.

MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes.

Akshaya Nambiar, René Martin, Kamakshi Tomar, Hans-Joachim Knölker, Sandhya P Koushika, Subramaniam K, Ravi Manjithaya.

  Autophagy requires precise regulation of autophagosome-lysosome fusion, yet the molecular details of this process remain incompletely understood. Here, we identify the class V myosin MYO5A as a critical regulator of autophagic flux. The genetic or pharmacological inhibition of MYO5A in Saccharomyces cerevisiae, mammalian cells, or Caenorhabditis elegans blocked autophagic flux by preventing autophagosome-lysosome fusion. MYO5A facilitates the maturation of autophagosomes into fusion-competent intermediates as its loss altered the localization of fusion machinery on autophagosomes and reduced the pool of stationary autophagosomes, a step that proved critical for subsequent fusion with lysosomes. Domain mapping and targeted mutagenesis revealed that two LIR motifs (PAYRVL and QAYIGL) within the coiled-coil and globular tail domains of MYO5A mediate its direct interaction with LC3 on autophagosomes. Live imaging in mammalian cells and C. elegans added support for this role, revealing how MYO5A regulates autophagic flux to ensure fusion. Together, these findings establish MYO5A as a regulator of autophagy and highlight its potential as a target for fine-tuning autophagic flux.

Keywords:  Actomyosin Dynamics; Autophagic Flux; Autophagosome–Lysosome Fusion; MYO5A; Unconventional Myosins

DOI:  https://doi.org/10.1038/s44318-025-00686-9