An ALS‐associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

• Published in: Genes to cells : devoted to molecular & cellular mechanisms Vol. 27; no. 6; pp. 421 - 435
• Main Authors: Nakano, Juri, Chiba, Kyoko, Niwa, Shinsuke
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.06.2022; John Wiley and Sons Inc
• Subjects: aggregation; ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Cell Line; Cell lines; Dyneins - genetics; Dyneins - metabolism; KIF5A; Kinesin; Kinesins - genetics; Kinesins - metabolism; Mice; Microtubules; mRNA; Mutants; Mutation; Neurons - metabolism; Neurons - pathology; Neurotoxicity; Oligomers; Original; Protein Aggregation, Pathological; Protein transport; ALS; aggregation; KIF5A
• ISSN: 1356-9597; 1365-2443; 1365-2443
• DOI: 10.1111/gtc.12936

KIF5A is a kinesin superfamily motor protein that transports various cargos in neurons. Mutations in Kif5a cause familial amyotrophic lateral sclerosis (ALS). These ALS mutations are in the intron of Kif5a and induce mis‐splicing of KIF5A mRNA, leading to splicing out of exon 27, which in human KIF5A encodes the cargo‐binding tail domain of KIF5A. Therefore, it has been suggested that ALS is caused by loss of function of KIF5A. However, the precise mechanisms regarding how mutations in KIF5A cause ALS remain unclear. Here, we show that an ALS‐associated mutant of KIF5A, KIF5A(Δexon27), is predisposed to form oligomers and aggregates in cultured mouse cell lines. Interestingly, purified KIF5A(Δexon27) oligomers showed more active movement on microtubules than wild‐type KIF5A in vitro. Purified KIF5A(∆exon27) was prone to form aggregates in vitro. Moreover, KIF5A(Δexon27)‐expressing Caenorhabditis elegans neurons showed morphological defects. These data collectively suggest that ALS‐associated mutations of KIF5A are toxic gain‐of‐function mutations rather than simple loss‐of‐function mutations. ALS‐associated KIF5A protein aggregates in cells and in vitro and has neurotoxicity.