Several motor proteins control anterograde axonal transport of TDP-43

By
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
October 9, 2026

Acta Neuropathologica

Overview

In H9-derived neurons, fluorescent TDP-43 showed processive anterograde axonal movement with kinetics comparable to vesicular cargoes. Biochemical and proximity-ligation analyses found associations with transport machinery, including KIF5A, KIF5B, and KIF5C through KLC1, as well as KIF1A. The findings support a multi-motor transport model for TDP-43-containing ribonucleoprotein complexes, while the contribution of transport disruption to ALS pathology remains unresolved.

Background

TDP-43 is an RNA-binding protein involved in RNA metabolism, with nuclear roles in transcription and splicing and cytoplasmic roles in mRNA trafficking and local translation. Its pathology is associated with ALS, FTLD-TDP-43, and LATE, among other neurodegenerative disorders. In approximately 97% of sporadic ALS cases, the source describes nuclear depletion alongside aberrant cytoplasmic accumulation and aggregation. These changes can affect both nuclear RNA processing and cytoplasmic mRNA transport, processes relevant to axonal and synaptic function.

Data Highlights

Measure or observation	Finding reported in source
Sporadic ALS with nuclear TDP-43 depletion and aberrant cytoplasmic accumulation	Approximately 97%
Neuronal model	H9 embryonic stem-cell-derived neurons
Axonal movement	Processive anterograde TDP-43 movement; kinetics comparable to vesicular cargoes
Kinesin associations	KIF5A, KIF5B, and KIF5C via KLC1; also KIF1A

Key Findings

Live-cell imaging and segmental trajectory analysis showed processive anterograde movement of TDP-43 in H9-derived neuronal axons.
TDP-43 movement kinetics were reported as comparable to those of vesicular cargoes, including Rab5, synaptophysin, and APP used as reference cargoes.
Biochemical assays and proximity-ligation analyses demonstrated interactions between TDP-43 and anterograde and retrograde transport machinery, consistent with a bidirectional transport profile.
TDP-43 interacted with all three kinesin-1 isoforms—KIF5A, KIF5B, and KIF5C—via kinesin light chain 1 (KLC1).
The study also found an interaction with KIF1A, a kinesin-3 family member.
The source proposes that TDP-43-containing membraneless organelles may use a flexible multi-motor transport arrangement; whether transport disruption contributes to ALS pathology remains uncertain.

Clinical Implications

The findings characterize candidate motor-protein associations and axonal transport behavior in a neuronal cell model; the source does not establish a clinical diagnostic or treatment application. The relationship between altered TDP-43 transport and ALS disease mechanisms remains an open question in the material provided.

Conclusion

TDP-43 undergoes anterograde axonal transport and associates with multiple kinesin motors, alongside evidence of interaction with retrograde machinery. The results support a multi-motor model but do not resolve how transport changes relate to neurodegeneration.