期刊
CELL
卷 157, 期 3, 页码 651-663出版社
CELL PRESS
DOI: 10.1016/j.cell.2014.03.049
关键词
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资金
- National Institutes of Health (NIH) [P01HD070494, R01NS048453, P30NS047101]
- Broad Institute [U54HG003067, GM049369]
- Yale Center for Mendelian Disorders [U54HG006504, RC2NS070477]
- Gregory M. Kiez and Mehmet Kutman Foundation
- French National Research Agency [ANRRVP13016KKA]
Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.
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