| Literature DB >> 24766810 |
Ashleigh E Schaffer1, Veerle R C Eggens2, Ahmet Okay Caglayan3, Miriam S Reuter4, Eric Scott1, Nicole G Coufal1, Jennifer L Silhavy1, Yuanchao Xue5, Hulya Kayserili6, Katsuhito Yasuno3, Rasim Ozgur Rosti1, Mostafa Abdellateef1, Caner Caglar3, Paul R Kasher2, J Leonie Cazemier2, Marian A Weterman2, Vincent Cantagrel7, Na Cai1, Christiane Zweier4, Umut Altunoglu6, N Bilge Satkin6, Fesih Aktar8, Beyhan Tuysuz9, Cengiz Yalcinkaya10, Huseyin Caksen11, Kaya Bilguvar3, Xiang-Dong Fu5, Christopher R Trotta12, Stacey Gabriel13, André Reis4, Murat Gunel3, Frank Baas2, Joseph G Gleeson14.
Abstract
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.Entities:
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Year: 2014 PMID： 24766810 PMCID： PMC4128918 DOI： 10.1016/j.cell.2014.03.049
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582