| Project/Area Number |
18K06507
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 46020:Anatomy and histopathology of nervous system-related
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| Research Institution | Kyorin University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
村田 麻喜子 杏林大学, 保健学部, 講師 (00276205)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 筋萎縮性側索硬化症 / アデノウイルス / TDP-43 / Praja1 / FUS / SOD1 / α-synuclein / polyglutamine / 運動ニューロン / 蛋白質凝集体 / 組換えウイルス / プロテアソーム / HSF1 / 筋萎縮性側索硬化症 (ALS) / Praja1 (PJA1) / 熱ショック応答 / 凝集体 / Praja 1 (PJA1) / ALS / 組換えアデノウイルス |
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| Outline of Final Research Achievements |
The formation of misfolded protein aggregates is one of the pathological hallmarks of neurodegenerative diseases. We demonstrated that, in neuronal cell culture and mouse models, Praja1 RING-finger E3 ubiquitin ligase (PJA1) suppresses the cytoplasmic aggregate formation of transactivation response DNA-binding protein of 43kDa (TDP-43), the main constituent of neuronal cytoplasmic aggregates in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Furthermore, PJA1 also suppressed the aggregate formation of fused in sarcoma, superoxide dismutase 1, α-synuclein, and ataxin-3 and huntingtin polyglutamine proteins in neuronal cultures. These results suggest that PJA1 is a common sensing factor for aggregate-prone proteins to counteract their aggregation propensity and could be a potential therapeutic target for neurodegenerative diseases that include ALS, FTLD, Parkinson’s disease, and polyglutamine diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
筋萎縮性側索硬化症，パーキンソン病，ポリグルタミン病などの神経変性疾患では，神経細胞内に各々TDP-43, FUS, SOD1, α-synuclein, ataxin 3, huntingtinなどの疾患特異的蛋白質からなる不溶性凝集体が形成され，凝集体の細胞間伝播とともに神経細胞変性が進行する．本研究ではPraja1 E3ユビキチンリガーゼ (PJA1) がこれら蛋白質の凝集を抑制することを見出し，PJA1による蛋白凝集抑制メカニズムの解明・応用が神経変性疾患全般の治療法開発に寄与する可能性が示唆された．
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