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2018 Fiscal Year Final Research Report

Role of cross-seeding in the pathogenesis of neurodegenerative disorders

Research Project

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Project/Area Number 17K15077
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Structural biochemistry
Research InstitutionTokushima Bunri University (2018)
Keio University (2017)

Principal Investigator

Eiichi Tokuda  徳島文理大学, 薬学部, 講師 (00757510)

Project Period (FY) 2017-04-01 – 2019-03-31
Keywordsクロスシーディング / タンパク質凝集体 / ミスフォールドタンパク質 / 神経変性疾患
Outline of Final Research Achievements

Mutations in the gene encoding superoxide dismutase-1 (SOD1) is causative for amyotrophic lateral sclerosis (ALS). Accumulation of conformational disordered SOD1 protein (i.e. misfolded SOD1) in motor neurons is a hallmark of ALS with SOD1 mutations. Several lines of evidence suggest that misfolded proteins observed in neurodegenerative diseases have prion-like properties: namely, misfolded proteins act as conformational templates that convert normal proteins into a pathogenic form.
To clarify whether the prion paradigm could be applicable for the misfolding of SOD1 in vivo, I investigated double transgenic mice expressing both mutant and wild-type SOD1. I found that misfolding of wild-type SOD1 was induced by the expression of mutant SOD1 even at an early stage of the disease and exaggerated ALS-like motor neuron symptoms.

Free Research Field

神経科学、生化学

Academic Significance and Societal Importance of the Research Achievements

SOD1変異を伴うALS患者は、約98%が優性遺伝であるため、変異型と野生型SOD1が共発現している。本課題では、マウスに変異型と野生型SOD1を共発現させると、変異型SOD1が野生型SOD1のミスフォールディングを誘発し、マウスの運動マヒ発症を早めることを明らかにした。本成果は動物実験ではあるが、SOD1変異を伴うALS患者の遺伝形式を再現している。野生型SOD1のミスフォールディングはALS発症に関与していることから、将来、野生型SOD1のミスフォード状態を測定することで、ALSの発症時期が予測できるようになるかもしれない。

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Published: 2020-03-30  

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