2021 Fiscal Year Final Research Report

Suppression of protein aggregate formation in ALS and other neurodegenerative disease models

Research Project

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Project/Area Number	18K06507
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 46020:Anatomy and histopathology of nervous system-related
Research Institution	Kyorin University
Principal Investigator	Watabe Kazuhiko 杏林大学, 保健学部, 教授 (30240477)
Co-Investigator(Kenkyū-buntansha)	村田麻喜子杏林大学, 保健学部, 講師 (00276205)
Project Period (FY)	2018-04-01 – 2022-03-31
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
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.
Free Research Field	神経病理学・神経化学・神経内科学
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．