"Unstructural biology" of alpha-synuclein, an intrinsically disordered protein related to the pathogenesis of Parkinson's disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03232
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43040:Biophysics-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: Fujiwara Satoru 国立研究開発法人量子科学技術研究開発機構, 量子生命科学研究所, 専門業務員 (10354888)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: シヌクレイン / 天然変性蛋白質 / 蛋白質重水素化 / 中性子散乱 / パーキンソン病

Outline of Final Research Achievements

Formation of abnormal filamentous aggregates (amyloid fibrils) of the protein, α-synuclein (αSyn), which is an intrinsically disordered protein (IDP), is closely related to the pathogenesis of Parkinson's disease. To elucidate how amyloid fibrils of αSyn form, the behavior of the αSyn monomers is investigated using small-angle neutron scattering and quasielastic neutron scattering. In particular, a new method, by which the detailed characterization of the structural distribution and the dynamical behavior of the IDPs such as αSyn is possible, is developed. This new method, utilizing the protein-deuteration techniques, is applied to various deuterated αSyn under various conditions, showing distinct propensity to fibril formation. The results obtained demonstrate the feasibility of the method, and provide the clues to specify the key behavior of αSyn leading to fibril formation.

Free Research Field

生物物理学

Academic Significance and Societal Importance of the Research Achievements

本研究で開発された新しい解析法により、パーキンソン病発症に深く関係するαSynのアミロイド線維形成開始のカギとなるふるまいが特定された。これはαSynのアミロイド線維形成機構解明に向けた重要な手掛かりとなり、将来のパーキンソン病の予防・治療戦略策定に大きな貢献をなしうる重要な成果である。また、この解析法は、α-シヌクレインのみならず様々な蛋白質のアミロイド線維形成機構解明や変性状態の蛋白質の解析など、様々な展開へとつながる解析法であり、蛋白質科学の更なる発展に大きく貢献しうる方法である。