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

• 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• 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 / AUUCUリピート / RNA / スプライシング異常 / 脊髄小脳失調10型 / SCA36 / GGCCTGリピート伸長 / RNA foci / RNA結合タンパク / リピート不安定性

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.

Research Products

• [Journal Article] Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage response pathway in SCA3. (2015)
  • Author(s): Gao R, Liu Y, Silva-Fernandes A, Fang X, Paulucci-Holthauzen A, Chatterjee A, Zhang HL, Matsuura T, Choudhary S, Ashizawa T, Koeppen AH, Maciel P, Hazra TK, Sarkar PS.
  • Journal Title: PLoS Genet Volume: 11 Issue: 1 Pages: e1004834-e1004834
  • DOI: 10.1371/journal.pgen.1004834
  • Peer Reviewed / Open Access
• [Journal Article] LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity (2014)
  • Author(s): Yamashita Y, Matsuura T, Kurosaki T, Amakusa Y, Kinoshita M, Ibi T, Sahashi K, Ohno K.
  • Journal Title: Neurobiol Disord Volume: 69 Pages: 200-205
  • DOI: 10.1016/j.nbd.2014.05.026
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour. (2013)
  • Author(s): Hernandez-Hernandez O, Guiraud-Dogan C, Sicot G, Huguet A, Luilier S, Steidl E, Saenger S, Marciniak E, Obriot H, Chevarin C, Nicole A, Revillod L, Charizanis K, Matsuura T, et al.
  • Journal Title: Brain Volume: 136 (Pt 3) Issue: 3 Pages: 957-970
  • DOI: 10.1093/brain/aws367
  • Peer Reviewed
• [Journal Article] Exome sequencing as a diagnostic tool to identify a causal mutation in genetically highly heterogeneous limb-girdle muscular dystrophy. (2013)
  • Author(s): Matsuura T, Kurosaki T, Omote Y, Minami N, Hayashi YK, Nishino I, Abe K.
  • Journal Title: J Hum Genet Volume: 58 Issue: 8 Pages: 564-565
  • DOI: 10.1038/jhg.2013.33
  • NAID: 10031195288
  • Peer Reviewed
• [Journal Article] Tissue Plasminogen Activator Thrombolytic Therapy for Acute Ischemic Stroke in 4 Hospital Groups in Japan. (2013)
  • Author(s): Kono S, Deguchi K, Morimoto N, Kurata T, Deguchi S, Yamashita T, Ikeda Y, Matsuura T, Narai H, Omori N, Manabe Y, Yunoki T, Takao Y, Kawata S, Kashihara K, Abe K.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 22 Issue: 3 Pages: 190-196
  • DOI: 10.1016/j.jstrokecerebrovasdis.2011.07.016
  • Peer Reviewed
• [Journal Article] Myotonic dystrophy type 2 (DM2) is rare in the Japanese population (2012)
  • Author(s): Matsuura T, Minami N, Arahata H, Ohno K, Abe K, Hayashi YK, Nishino I
  • Journal Title: J Hum Genet Volume: (印刷中) Issue: 3 Pages: 219-220
  • DOI: 10.1038/jhg.2011.152
  • Peer Reviewed
• [Journal Article] Four parameters increase the sensitivity and specificity of the exon array analysis and disclose twenty-five novel aberrantly spliced exons in myotonic dystrophy. (2012)
  • Author(s): Yamashita Y, Matsuura T, Shinmi J, Amakusa Y, Masuda A, Ito M, Kinoshita M, Furuya H, Abe K, Ibi T, Sahashi K, Ohno K.
  • Journal Title: Journal of Human Genetics Volume: 57 Issue: 6 Pages: 368-374
  • DOI: 10.1038/jhg.2012.37
  • Peer Reviewed
• [Journal Article] The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome (2012)
  • Author(s): Kurosaki, T., Ueda, S., Ishida, T., Abe, K., Ohno, K. and Matsuura, T
  • Journal Title: PLos One Volume: 7 Issue: 6 Pages: e38379-e38379
  • DOI: 10.1371/journal.pone.0038379
  • Peer Reviewed
• [Presentation] RNA disease mechanism in DM1 and SCA10 brain (2015)
  • Author(s): Tohru Matsuura
  • Organizer: 第38回日本神経科学大会シンポジウム講演
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-29
  • Int'l Joint Research / Invited
• [Presentation] 筋強直性ジストロフィーの分子病態～治療 (2015)
  • Author(s): 松浦 徹
  • Organizer: 第6回遺伝カウンセリングアドバンスドセミナー
  • Place of Presentation: 大阪
  • Year and Date: 2015-01-10
  • Invited
• [Presentation] RNA-mediated disease mechanism of spinocerebellar ataxia type 10. (2012)
  • Author(s): Matsuura T, Kurosaki T, Muramatsu S, Shimazaki K, Ohno K, Abe K.
  • Organizer: 7th International Conference on Unstable Microsatellites & Human Disease
  • Place of Presentation: Strasbourg, France