Role of cross-seeding in the pathogenesis of neurodegenerative disorders
| Project/Area Number |
17K15077
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Structural biochemistry
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| Research Institution | Tokushima Bunri University (2018)
Keio University (2017) |
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Principal Investigator |
Eiichi Tokuda 徳島文理大学, 薬学部, 講師 (00757510)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| 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 / 筋萎縮性側索硬化症 / マウスモデル / プリオン様特性 |
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| 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.
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| 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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Report
(3 results)
Research Products
(19 results)
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[Journal Article] Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA312017
Author(s)
Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, 他８名
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Journal Title
Neuron
Volume: 94
Issue: 1
Pages: 108-124
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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