Multiple motor proteins regulate TDP-43 anterograde axonal transport

Abstract

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.

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BibTeX

@article{feole2026multiple,
  title = {{Multiple motor proteins regulate TDP-43 anterograde axonal transport}},
  author = {Monica Feole and Victorio M Pozo Devoto and Neda Dragišić and Maria Čarna and Katja Klosterman and Clara Limbaek-Stokin and Giancarlo Forte and Kenneth L Moya and Richard A Smith and Clive N Svendsen and Gorazd B Stokin},
  journal = {Acta Neuropathologica},
  year = {2026},
  month = oct,
  doi = {10.1007/s00401-026-03071-w},
  url = {https://hal.science/hal-05793998v1},
  note = {CC BY-NC-ND 4.0},
}

RIS

TY  - JOUR
TI  - Multiple motor proteins regulate TDP-43 anterograde axonal transport
AU  - Monica Feole
AU  - Victorio M Pozo Devoto
AU  - Neda Dragišić
AU  - Maria Čarna
AU  - Katja Klosterman
AU  - Clara Limbaek-Stokin
AU  - Giancarlo Forte
AU  - Kenneth L Moya
AU  - Richard A Smith
AU  - Clive N Svendsen
AU  - Gorazd B Stokin
PY  - 2026
DA  - 2026/10/09
JO  - Acta Neuropathologica
DO  - 10.1007/s00401-026-03071-w
UR  - https://hal.science/hal-05793998v1
AB  - 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.
SN  - 0001-6322
SN  - 1432-0533
ER  -

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