Exploring a pathogenic mechanism underlying neurodegenerative disorders caused by mutated RNA repeat

• Project/Area Number: 15K09335
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ISHIKAWA Kinya 東京医科歯科大学, 医学部附属病院, 教授 (30313240)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 遺伝子 / 脳 / 神経疾患 / ＲＮＡ / 神経変性疾患 / 脊髄小脳変性症 / モデル動物 / 遺伝子異常 / RNA / 抗体 / 分子標的治療

Outline of Final Research Achievements

Spinocerebellar ataxia type 31 (SCA31) is caused by the presence of a penta-nucleotide repeat (TGGAA)n in an intron shared by two genes, BEAN1 (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2). The critical repeat (TGGAA)n is expressed as (UGGAA)n in BEAN1 direction. In situ hybridization shows that abnormal RNA structures (RNA foci) in SCA31 patients' Purkinje cell nuclei consist of (UGGAA)n. In this study, we undertook RNA expression analysis focusing on TK2-transcripts in RNA-seq data. We also examined protein F that was identified to bind with (UUCCA)n, the TK2-direction mutant repeat. We found subtle protein F mislocalization in transgenic mice expressing (UUCCA)n. Conventional RNA seq and exon array from human samples suggested only a mild splicing abnormality. Therefore, a single molecule RNA seq analysis was undertaken from human samples. Twenty-two genes whose splicing is regulated by protein F will be first analyzed for mis-regulation.

Research Products

• [Journal Article] A novel mutation in ELOVL4 leading to spinocerebellar ataxia (SCA) with the hot cross bun sign but lacking erythrokeratodermia: a broadened spectrum of SCA34. (2015)
  • Author(s): Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T, Yamane K, Irioka T, Ishiura H, Doi K, Morishita S, Higashi M, Sekiguchi T, Koyama K, Ueda N, Miura Y, Miyatake S, Matsumoto N, Yokota T, Tanaka F, Tsuji S, Mizusawa H, Ishikawa K.
  • Journal Title: JAMA Neurology Volume: 72 Issue: 7 Pages: 797-805
  • DOI: 10.1001/jamaneurol.2015.0610
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant