Journal Articles Cell Year : 2014

CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration

Ashleigh E Schaffer
  • Function : Author
Veerle R C Eggens
  • Function : Author
Ahmet Okay Caglayan
  • Function : Author
Miriam S Reuter
  • Function : Author
Eric Scott
  • Function : Author
Nicole G Coufal
  • Function : Author
Jennifer L Silhavy
  • Function : Author
Yuanchao Xue
  • Function : Author
Hulya Kayserili
  • Function : Author
Katsuhito Yasuno
  • Function : Author
Rasim Ozgur Rosti
  • Function : Author
Mostafa Abdellateef
  • Function : Author
Caner Caglar
  • Function : Author
Paul R Kasher
  • Function : Author
J Leonie Cazemier
  • Function : Author
Marian A Weterman
  • Function : Author
Na Cai
  • Function : Author
Christiane Zweier
  • Function : Author
Umut Altunoglu
  • Function : Author
N Bilge Satkin
  • Function : Author
Fesih Aktar
  • Function : Author
Beyhan Tuysuz
  • Function : Author
Cengiz Yalcinkaya
  • Function : Author
Huseyin Caksen
  • Function : Author
Kaya Bilguvar
  • Function : Author
Xiang-Dong Fu
  • Function : Author
Christopher R Trotta
  • Function : Author
Stacey Gabriel
  • Function : Author
André Reis
  • Function : Author
Murat Gunel
  • Function : Author
Frank Baas
  • Function : Author
Joseph G Gleeson
  • Function : Author

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. Copyright © 2014 Elsevier Inc. All rights reserved.

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hal-04972118 , version 1 (28-02-2025)

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Ashleigh E Schaffer, Veerle R C Eggens, Ahmet Okay Caglayan, Miriam S Reuter, Eric Scott, et al.. CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration. Cell, 2014, 157 (3), ⟨10.1016/j.cell.2014.03.049⟩. ⟨hal-04972118⟩

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