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

Abstract

SUMMARY Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of over 2000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit (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 links tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

“…Schaffer et al 2014). Although reported previously to be expressed ubiquitously (Thisse and Thisse 2004), in situ hybridization of rpl10 riboprobes in 2 dpf embryos demonstrated enriched expression in the anterior vs. posterior structures, particularly at the midbrain-hindbrain boundary ( Figure S1).…”

Healing for destruction: tRNA intron degradation in yeast is a two-step cytoplasmic process catalyzed by tRNA ligase Rlg1 and 5′-to-3′ exonuclease Xrn1

“…In the second, hClp1, a component of the mammalian SEN complex, catalyzes phosphorylation of the 59 end of the 39 exon of tRNAs, although the ligase is not identified (Zillmann et al 1991;Weitzer and Martinez 2007;Ramirez et al 2008). New studies reported that CLP1 mutation leads to severe neurodegenerative disease, and fibroblasts from human patients accumulate linear introns with a 59 hydroxyl, although intron accumulation was not observed in in vitro analyses (Karaca et al 2014;Schaffer et al 2014). We wonder whether introns are targets of CLP1 in vertebrate cells and whether it is possible that defects in tRNA intron turnover might contribute to the neurological phenotypes caused by CLP1 mutations.…”

The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health

“…Patient-derived neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated oxidative stress-induced cell death (76). The biogenesis of these tRNA fragments is distinct from that of ANG-induced tiRNAs; however, collective findings in the field suggest that tRNA metabolism and development of neurodegenerative diseases are strongly related.…”