Research on prion-like propagation of distinct alpha-synuclein strains derived from human synucleinopathies

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15359
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: The University of Tokyo
• Principal Investigator: Tarutani Airi 東京大学, 大学院薬学系研究科(薬学部), 特任助教 (10815187)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: プリオン様伝播 / 神経変性疾患 / αシヌクレイン / プリオン / strain(株)

Outline of Final Research Achievements

The concept that abnormal protein aggregates show prion-like propagation between cells has been considered to explain the onset and progression of many neurodegenerative diseases. Indeed, both synthetic amyloid-like fibrils and pathogenic proteins extracted from patients’ brains induce self-templated amplification and cell-to-cell transmission in vitro and in vivo. We investigated in detail the prion-like seeding activities of pathogenic α-synuclein(α-syn) extracted from patients with α-synucleinopathy. Pathogenic α-syn seeds derived from dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) showed structurally and biochemically distinct prion-like properties. Moreover, pathogenic α-syn derived from MSA exhibited higher seeding activity than those derived from DLB in cultured cells and wild-type mouse brains. These results indicate the presence of α-syn strains in α-synucleinopathy.

Free Research Field

病態神経科学

Academic Significance and Societal Importance of the Research Achievements

神経変性疾患における臨床的、病理学的多様性はプリオンの性質の１つである異なる高次構造をもつ異常型タンパク質の”strains”(株)で説明可能である。本研究ではαシヌクレイノパチー患者脳から抽出した病原性シードを網羅的に用いることにより、αシヌクレインのstrainにおけるプリオン様性質の違いが明らかとなり、患者脳シードを用いたプリオン様伝播実験モデルの有用性が示された。