Study of molecular pathology using proteome analyses for protein complexes in Spinocerebellar ataxia type 1

2014 Fiscal Year Final Research Report

• Project/Area Number: 24500378
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KAZUHIKO Tagawa 東京医科歯科大学, 難治疾患研究所, 准教授 (80245795)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: ポリグルタミン病 / 脊髄小脳失調症１型 / アタキシン－１ / タンパク質相互作用 / タンパク質複合体

Outline of Final Research Achievements

Spinocerebellar ataxia type 1 (SCA1) is one of nine polyglutamine diseases. Ataxin-1 (Atxn1) is a causative gene for SCA1. In order to understand functions of atxn1 complex, we set up proteome analyses. We identified and quantified proteins and constructed a pathogenic networks using system biology. However, we have not succeeded to analyze atxn1-complex. In this study, we described the interacting protein to atxn1 and functions of Atxn1-complex.
(1) VCP interacts to normal and mutant atxn1. Mutant Atxn1 finally caused the increase of DNA damege. (2) We performed a systematic in vivo screen of fly library in SCA1 fly models. Using systems biology analyses, RpA1 was located at the hub position. Atxn1 actually interacted With RpA1. (3) Mutant Atxn1 binds HMGB1. We established that complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in SCA1 model mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis.

Free Research Field

分子神経病理学