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

• Published in: Cell Vol. 157; no. 3; pp. 651 - 663
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.04.2014
• Subjects: Animals; Brain - metabolism; Brain - pathology; Cerebellum - growth & development; Cerebellum - pathology; Cleavage And Polyadenylation Specificity Factor - genetics; Cleavage And Polyadenylation Specificity Factor - metabolism; Danio rerio; Female; Humans; Male; Mice; Models, Molecular; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pedigree; Phosphotransferases - genetics; Phosphotransferases - metabolism; RNA Splicing; RNA, Transfer - genetics; RNA, Transfer - metabolism; Saccharomyces cerevisiae - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.03.049

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.