2022 Fiscal Year Final Research Report

Stress dependent production and release of aggregated proteins in neurodegenerative disorders

Research Project

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Project/Area Number	20H00525
Research Category	Grant-in-Aid for Scientific Research (A)
Allocation Type	Single-year Grants
Section	一般
Review Section	Medium-sized Section 52:General internal medicine and related fields
Research Institution	The University of Tokyo
Principal Investigator	Iwatsubo Takeshi 東京大学, 大学院医学系研究科(医学部), 教授 (50223409)
Co-Investigator(Kenkyū-buntansha)	山田薫東京大学, 大学院医学系研究科(医学部), 助教 (00735152) 桑原知樹東京大学, 大学院医学系研究科(医学部), 講師 (10533903) 若林朋子東京大学, 大学院医学系研究科(医学部), 特任准教授 (20530330) 橋本唯史東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	細胞ストレス / 神経変性 / アルツハイマー病 / パーキンソン病 / タウ蓄積症
Outline of Final Research Achievements	We examined the effects of cellular stress on the aggregation and release of pathogenic proteins. In Alzheimer's brains, metabolic stress aggravated ER stress and systemic to brain transmission of noxious signals to enhance amyloid pathology. Tau proteins were shown to be cleared through the glymphatic system, which was enhanced by amyloid stress. Alpha-synuclein aggregates were released by LRRK2-Rab10 signal in a reciprocal manner. Phosphorylation of FUS protein attenuated its insolubility. These findings underscored the importance of various cellular stresses in the aggregation and release of causative proteins.
Free Research Field	神経病理学
Academic Significance and Societal Importance of the Research Achievements	アルツハイマー病、パーキンソン病等個別の神経変性疾患に固有の病因タンパク質形成、放出機構の解明を進めることにより、各疾患に特異的な病態が明らかになるとともに、各種の細胞ストレスが神経変性を助長するとの仮説の一端が実証され、今後の神経変性疾患の予防、治療法の開発の方向性に指針を与えることができた。