Repeat instability and RNA-mediated disease mechanism of non-coding repeat expansion ataxias

2015 Fiscal Year Final Research Report

• Project/Area Number: 24390083
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: Jichi Medical University
• Principal Investigator: Tohru Matsuura 自治医科大学, 医学部, 教授 (90402560)
• Co-Investigator(Renkei-kenkyūsha): OHNO Kinji 名古屋大学, 大学院医学研究科, 教授 (80397455)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: 脊髄小脳失調症 / 脊髄小脳失調症10型 / 非翻訳領域リピート伸長 / RNA病態

Outline of Final Research Achievements

Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited neurodegenerative
disorder caused by unstable expansion of ATTCT repeats in intron 9 of ATXN10 gene on chromosome 22q13.31. The mechanism by which the ATTCT expansion causes the SCA10 phenotype is still unknown. Here we present data suggesting that expanded AUUCU RNA triggers neuronal dysfunctions. We detected intranuclear AUUCU inclusions in SCA10 cells by RNA-FISH, similar to other non-coding repeat expansion disorders. Furthermore, we characterized their intranuclear localization and nucleic acid contents, demonstrating that the inclusions are located at perinucleolar compartments and enriched for the AUUCU expansion, but not intronic flanking sequences. Several RNA-binding proteins were found to bind AUUCU repeats, including splicing factor PTBP1, which regulates neuronal-specific PTBP2 splicing during neurodevelopment. SCA10 cells showed aberrant splicing of PTBP2 and significantly increased PTBP2 protein levels.

Free Research Field

遺伝性神経筋疾患の分子病態機構解明