The analysis of aberrant machinery mediated by intraneural and extraneural alpha-synuclein oilgomers

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07753
• 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: Department of Clinical Research, National Hospital Organization Utano National Hospital
• Principal Investigator: Yamamoto Kenji 独立行政法人国立病院機構(宇多野病院臨床研究部), その他部局等, 研究員(移行) (50378775)
• Co-Investigator(Kenkyū-buntansha): 澤田 秀幸 独立行政法人国立病院機構(宇多野病院臨床研究部), その他部局等, その他 (30335260)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: αシヌクレイン / アミロイドβ / オリゴマー / カルシウムチャンネル / カリウムチャンネル / アミロイド前駆体蛋白 / Homer / パッチクランプ

Outline of Final Research Achievements

α-Synuclein oligomers (αSo) and amyloid-β oligomers (Aβo), and dysregulated activity-dependent Ca2+ homeostasis play pivotal roles in the neuronal damage occurring in Lewy body disease and Alzheimer's disease. The current study used electrophysiological and immunochemical analyses to evaluate how intracellular αSo and Aβo act on the neuronal excitability and Ca2+ dynamics in neocortical pyramidal neurons. This study suggest that intracellularly applied higher-order αSo causes the aberrant form of Ca2+-induced Ca2+ release from IP3 receptor during multiple spikes, which suggest the complicity of αSo and Ca2+ dyshomeostasis in selective neuronal vulnerability in Lewy body disease, and intracellular Aβo indirectly suppresses BK-type potassium channel via the association with amyloid precursor protein and Homer protein, which can cause Ca2+ dysregulation mediated by spike-induced excess Ca2+ influx.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、申請者らがこれまで確立してきた細胞電気生理学的手法を用いて、パーキンソン病やアルツハイマー型認知症で神経変性を生ずる原因とされている細胞内の凝集タンパクが、神経細胞死を生ずる以前に、神経細胞内のどの分子に特異的に作用して、神経活動の際のカルシウム制御不全という機能障害をもたらす標的を直接検証することによって、神経変性の進行を防御する新たな治療の足がかりを提供できる。