| Autor: |
Desiree M. Baron, Adam R. Fenton, Sara Saez-Atienzar, Anthony Giampetruzzi, Aparna Sreeram, Shankaracharya, Pamela J. Keagle, Victoria R. Doocy, Nathan J. Smith, Eric W. Danielson, Megan Andresano, Mary C. McCormack, Jaqueline Garcia, Valérie Bercier, Ludo Van Den Bosch, Jonathan R. Brent, Claudia Fallini, Bryan J. Traynor, Erika L.F. Holzbaur, John E. Landers |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 39, Iss 1, Pp 110598- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2022.110598 |
| Popis: |
Summary: 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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