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

Abstract

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.

Disruption of axonal transport in neurodegeneration

“…For example, axonal transport is perturbed by mutations in SOD1 (encoding superoxide dismutase 1) that cause ALS (129)(130)(131). Likewise, ALS-causing mutations of FUS and TDP-43 also alter axonal transport (132)(133)(134). Potential mechanisms for these impairments are discussed below.…”

Patogenia das doenças relacionadas ao citoesqueleto: uma revisão da literatura/ Pathogenics of cytoskeleton-related diseases: a review

“…Essas estruturas esféricas são encontradas no corno anterior da medula espinal de doentes com Brazilian Journal of Development, Curitiba, v.7, n.6, p. 60578-60593 jun. 2021Esclerose Lateral Amiotrófica (RIBEIRO et al, 2020;SILVA et al, 2021;SEIFERT et al, 2021).…”