Modeling a human CLP1 mutation in mouse identifies an accumulation of tyrosine pre-tRNA fragments causing pontocerebellar hypoplasia type 10
| Autor: | Takatoshi Hikida, Hiroshi Shiraishi, Minoru Fujiki, Takashi Kobayashi, Hiroyuki Fujinami, Ikuko Morisaki, Josef M. Penninger, Toshikatsu Hanada, Reiko Hanada, Nobuyuki Shimizu, Yuji Arai |
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| Rok vydání: | 2021 |
| Předmět: |
Polyadenylation
Biophysics Pontocerebellar hypoplasia Motor Activity Biology medicine.disease_cause Models Biological Biochemistry RNA Transfer Cerebellar Diseases RNA Precursors medicine Animals Humans Amino Acid Sequence Molecular Biology Motor Neurons Mice Inbred ICR Messenger RNA Mutation Base Sequence Phosphotransferases Intron Nuclear Proteins RNA Cell Biology Fibroblasts medicine.disease Introns Cell biology Mice Inbred C57BL Phenotype Transfer RNA RNA splicing Microcephaly Tyrosine Transcription Factors |
| Zdroj: | Biochemical and Biophysical Research Communications. 570:60-66 |
| ISSN: | 0006-291X |
| Popis: | Cleavage factor polyribonucleotide kinase subunit 1 (CLP1), an RNA kinase, plays essential roles in protein complexes involved in the 3'-end formation and polyadenylation of mRNA and the tRNA splicing endonuclease complex, which is involved in precursor tRNA splicing. The mutation R140H in human CLP1 causes pontocerebellar hypoplasia type 10 (PCH10), which is characterized by microcephaly and axonal peripheral neuropathy. Previously, we reported that RNA fragments derived from isoleucine pre-tRNA introns (Ile-introns) accumulate in fibroblasts of patients with PCH10. Therefore, it has been suggested that this intronic RNA fragment accumulation may trigger PCH10 onset. However, the molecular mechanism underlying PCH10 pathogenesis remains elusive. Thus, we generated knock-in mutant mice that harbored a CLP1 mutation consistent with R140H. As expected, these mice showed progressive loss of the upper motor neurons, resulting in impaired locomotor activity, although the phenotype was milder than that of the human variant. Mechanistically, we found that the R140H mutation causes intracellular accumulation of Ile-introns derived from isoleucine pre-tRNAs and 5' tRNA fragments derived from tyrosine pre-tRNAs, suggesting that these two types of RNA fragments were cooperatively or independently involved in the onset and progression of the disease. Taken together, the CLP1-R140H mouse model provided new insights into the pathogenesis of neurodegenerative diseases, such as PCH10, caused by genetic mutations in tRNA metabolism-related molecules. |
| Databáze: | OpenAIRE |
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