Analysis of onset mechanism of paroxysmal kinesigenic dyskinesia using genetic animal models

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22688
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0704:Neuroscience, brain sciences, and related fields
• Research Institution: Nagasaki University
• Principal Investigator: Hatta Daisuke 長崎大学, 医歯薬学総合研究科(薬学系), 客員研究員 (60886216)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: PRRT2 / PKD / ジスキネジア / ドーパミン / L-ドーパ / ロータロッド

Outline of Final Research Achievements

Paroxysmal kinesigenic dyskinesia (PKD) is a neurological disease presenting unvoluntary movements triggered by sudden movements. We had previously generated Prrt2 knock-in (KI) mice harboring PKD-related Prrt2 mutation, which had much higher extracellular concentration of dopamine than wild-type mice during neuronal stimulation in the striatum. In the present study, we evaluated motor functions of Prrt2 KI mice by rotarod test. Although there was no significant difference in motor functions between wild-type and Prrt2 KI mice, intraperitoneal administration of L-dopa caused more severe motor deficit in Prrt2 KI mice than in wild-type mice. These results suggest that PKD is caused by excessive dopamine transmission in the striatum and subsequent hyper-activity of the cortico-basal ganglia motor loop.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

これまでPKDの原因となる神経回路や発症機序は十分に理解されておらず、国外からの報告では主に小脳に着目した解析がなされてきた。しかし本研究では、PKDモデルマウスにおいて線条体での過剰なドーパミン伝達が運動障害に関連することを明らかにし、PKDの発症機序の仮説として「線条体ドーパミン説」という新たな学術的概念を作ることができた。
本研究の成果はPKDの治療方法の基盤構築に繋がるだけでなく、痙攣や不随意運動を伴う類似疾患の治療薬開発にも応用可能と考えられ、医療の進歩という形で社会に貢献する研究となった。