2019 Fiscal Year Final Research Report
Identification of a metabolic pathway for aberrant RNA in frontotemporal dementia and its disruption
Project/Area Number |
17H05091
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Research Category |
Grant-in-Aid for Young Scientists (A)
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Allocation Type | Single-year Grants |
Research Field |
Psychiatric science
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Research Institution | Osaka University |
Principal Investigator |
Mori Kohji 大阪大学, 医学系研究科, 助教 (40775318)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Keywords | C90rf72 / RAN翻訳 / DPR / RNA代謝 / 核小体 |
Outline of Final Research Achievements |
An intronic GGGGCC (G4C2) repeat expansion in C9orf72 gene was identified as a leading genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The hexanucleotide DNA repeat is bidirectionally transcribed into repeat RNA accumulating within RNA foci. We revealed the repeat RNA is even translated into five distinct proteins called dipeptide-repeat protein (DPR)s in the absence of the canonical translation initiation codon (AUG). Since the identification of DPR, cytotoxic properties of DPR has been extensively shown in multiple disease models. In the current study, we identified a factor directly involved in the metabolism of the repeat RNA. Moreover, pathogenic DPR inhibits the enzymatic activity of the factor.
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Free Research Field |
精神神経科学、神経変性疾患、分子生物学
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Academic Significance and Societal Importance of the Research Achievements |
本研究の成果により、C9orf72変異における異常リピートRNAの代謝経路の一端が明らかとなった。本成果を応用することでRNA代謝異常を標的とした新規治療法の開発にもつながる可能性がある。また将来的にはC9orf72-FTD/ALSのみならず脊髄小脳変性症やハンチントン病など他のリピート病の病態解明にも寄与する可能性がある。研究成果は、学会発表や論文の出版を通じて学術界で知見を共有するとともに、一般社会に還元される。
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