Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell, 2014-04, Vol.157 (3), p.651-663

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •A human CLP1 mutation causes brain and motor neuron degeneration•Mutation impairs kinase activity, nuclear localization, and TSEN complex assembly•Patient iNeurons have accumulated pre-tRNA and reduced mature tRNA•Clp1 mutant zebrafish display p53-dependent neurodegeneration A mutation in the human RNA kinase Clp1 perturbs tRNA biogenesis and promotes susceptibility to apoptosis, leading to a complex neurological phenotype.