CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration

Cell.
Authors
Ashleigh E. Schaffer,1 Veerle R.C. Eggens,2 Ahmet Okay Caglayan,3 Miriam S. Reuter,4 Eric Scott,1 Nicole G. Coufal,1
Jennifer L. Silhavy,1 Yuanchao Xue,5 Hulya Kayserili,6 Katsuhito Yasuno,3 Rasim Ozgur Rosti,1 Mostafa Abdellateef,1
Caner Caglar,3 Paul R. Kasher,2 J. Leonie Cazemier,2 Marian A. Weterman,2 Vincent Cantagrel,1,7 Na Cai,1
Christiane Zweier,4 Umut Altunoglu,6 N. Bilge Satkin,6 Fesih Aktar,8 Beyhan Tuysuz,9 Cengiz Yalcinkaya,10
Huseyin Caksen,11 Kaya Bilguvar,3 Xiang-Dong Fu,5 Christopher R. Trotta,12 Stacey Gabriel,13 Andre´ Reis,4
Murat Gunel,3,14 Frank Baas,2,14 and Joseph G. Gleeson1,14,*
1Neurogenetics Laboratory, Howard Hughes Medical Institute, Department
03-09-2016
12:00pm
PST
Categories
tRNA Processing & Function
Speaker
Brian Grone
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.