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Brain Proteinopathy 2014
Brain Proteinopathy 2014

開催日 2014/9/11
時間 17:00 - 19:00
会場 Room E(301)
Chairperson(s) 田中 元雅 / Motomasa Tanaka (独立行政法人理化学研究所 脳科学総合研究センター タンパク質構造疾患研究チーム / Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Japan)
貫名 信行 / Nobuyuki Nukina (順天堂大学大学院医学研究科 神経変性疾患病態治療探索講座 / Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Japan)

Aggregate-associated proteins as potential modifiers of polyglutamine diseases

  • S1-E-3-5
  • 紀 嘉浩 / Yoshihiro Kino:1,2 貫名 信行 / Nobuyuki Nukina:2 
  • 1:明治薬科大学・薬学部・バイオインフォマティクス / Dept Bioinformatics and Mol Neuropathol, Meiji Pharmaceutical University, Tokyo, Japan 2:順天堂大・医学研究科・神経変性疾患病態治療探索講座 / Dept Neurosci for Neurodegenerative Disorders, Juntendo Univ Grad Sch of Med, Tokyo, Japan 

Protein aggregation and inclusion body formation are hallmarks of neurodegenerative diseases. However, it is still unclear whether these pathological structures represent protective responses, bystanders, or toxic entities in the pathogenesis. We and others have identified several protein components of polyglutamine aggregates such as SQSTM1/p62, UBQLN2, FUS/TLS, OPTN, and VCP, which are genetically or pathologically associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus, polyglutamine inclusions appear to accumulate proteins related to neurodegenerative diseases, implying a potential link between polyQ disease and ALS/FTLD. Here we examined the role of FUS/TLS, an RNA/DNA-binding protein that binds to mutant huntingtin, in polyglutamine disease model mice. We found that heterozygous depletion of FUS/TLS differentially modified the phenotypes of model mice of two distinct polyglutamine diseases. This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS as well as gene expression changes caused by its deficiency, suggesting that co-aggregation of FUS/TLS with polyglutamine is a rate-limiting factor of disease phenotypes. These results highlight inclusions/aggregates as repositories of potential modifiers of neurodegenerative disorders and indicate a pathological protein interaction network that underlies the etiology of multiple proteinopathies.

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