ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function.
Cell Rep
; 39(1): 110598, 2022 04 05.
Article
em En
| MEDLINE
| ID: mdl-35385738
ABSTRACT
Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.
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MEDLINE
Assunto principal:
Esclerose Lateral Amiotrófica
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article