4.7 Article

The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility

Journal

Publisher

MDPI
DOI: 10.3390/ijms22052422

Keywords

motor neurons; axonopathy; molecular motors; axonal transport; gliding motility assays

Funding

  1. German Federal Ministry of Education and Research BMBF OptiZeD [03Z22E511]
  2. NOMIS foundation
  3. Helmholtz Virtual Institute RNA dysmetabolism in ALS and FTD [VH-VI-510]
  4. Hermann und Lilly Schilling-Stiftung fur medizinische Forschung im Stifterverband
  5. Stiftung zur Forderung der Hochschulmedizin in Dresden
  6. Center For Regenerative Therapies Dresden (CRTD)

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Deficient intracellular transport is a common feature of neurodegenerative diseases. Mutations in the FUS gene are a common genetic cause of ALS, but the negative effect of FUS (P525L) on axonal transport is indirect and requires additional factors or mechanisms.
Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility in vitro. Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms.

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