Characterization of cell-to-cell transmissible alpha-synuclein pathogenic seeds

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07299
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Taguchi Katsutoshi 京都府立医科大学, 医学(系)研究科(研究院), 講師 (60462701)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: パーキンソン病 / レビー小体 / α－シヌクレイン / シード / プリオン様細胞間伝播

Outline of Final Research Achievements

alpha-Synuclein (aSyn) is one of major constituents of Lewy bodies (LBs) and Lewy neurites (LNs), which are well-known pathological hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Accumulated evidence suggests that prion-like transmission of pathogenic seeds is a critical event for progressive neurodegeneration. However, properties of the seeds remain to be elucidated. Here, we isolated aSyn oligomers released from pathological neurons harboring LB-like aggregates. These extracellular oligomers had uniform molecular weight and induced LB-pathology in cultured neurons. Interestingly, mass spectrometric analysis demonstrated the presence of characteristic truncation forms of aSyn constituting those seeds. We further identified inhibitor for the candidate enzyme which catalyzes aSyn truncation. Thus, post-translational modification of aSyn will be a better therapeutic target to inhibit the disease propagation through the seed-transmission in PD and DLB brain.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病は黒質ドーパミン神経の脱落に起因する様々な運動症状を示す。これに対してはドーパ製剤の投与による対症療法で対処するのが主流であり、進行する神経変性を積極的に阻止する方法は未だ確立されていない。本研究は病的神経が自ら産生した病原性Seedを分離し、網羅的生化学検索によって検出することができたSeed に特徴的な分子修飾に着目しており、内在性αSynが病原性を獲得するメカニズムを明らかにするのみならず、伝播性Seedを標的とした新規神経保護ストラテジーの構築につながる所見を得ることができたと位置づけられ、PDの新規分子標的医薬開発の起点となる創造性を有している。