A trial of avoiding disease propagation targeted on the synuclein aggregation and lysophagy

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09321
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tsujimura Atsushi 京都府立医科大学, 医学(系)研究科(研究院), 助教 (50236890)
• Co-Investigator(Kenkyū-buntansha): 渡邊 義久 京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990) ; 田口 勝敏 京都府立医科大学, 医学(系)研究科(研究院), 助教 (60462701)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: パーキンソン病 / αシヌクレイン / オートファジー / ドーパミン

Outline of Final Research Achievements

When α-Syn aggregation nuclei were introduced into cells expressing α-Syn-GFP, fluorescence of intracellular aggregates like Levy bodies was observed. In autophagy KO cells, the amount of intracellular aggregation was significantly increased, and aggregates were shown to be processed mainly by autophagic process. Cytotoxicity increases with the reactivation of autophagy, and products resulting from degradation of aggregates and damaged lysosomes were considered to be a causative. It was also suggested that the oligomers produced by the seeds generated from the degradation products are toxic.
Also, in the presence of dopamine in cells, an increase in aggregates was observed. The cycle of aggregation / degradation / reaggregation is thought to cause vulnerability of DA-producing neurons, as cytotoxicity was also significantly increased with autophagy activation in these cells.

Free Research Field

分子神経学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病では、神経細胞中にαシヌクレインが凝集したレビー小体が出現し、凝集体の形成過程で毒性が発揮されると考えられるが、細胞内で隔離された凝集体は毒性を発揮しにくいとも考えられる。オートファジーで再分解が始まると凝集の核となる種（シード）が再出現し毒性の高いオリゴマーが作られる機会が増加して細胞毒性が増幅される可能性が示された。シードの再出現を抑制することによる病態抑制の可能性が示された。