Common Mechanism of Dyskinesia Onset between Antipsychotic Drugs and Parkinson's Disease Treatments

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15215
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Keio University
• Principal Investigator: Abe Yoshifumi 慶應義塾大学, 医学部(信濃町), 講師 (80802826)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: L-DOPA誘導性ジスキネジア / 遅発性ジスキネジア / 淡蒼球 / VGAT / GABA

Outline of Final Research Achievements

A hypothesis was tested that L-DOPA-induced dyskinesia (LID) and tardive dyskinesia (TD) share a common molecular mechanism mediated by GABA. In LID and TD model mice, it was found that an increase in globus pallidus volume, increased GABA levels, and hypertrophy of VGAT-positive terminals commonly occurred. Overexpression of VGAT led to increased GABA levels, terminal hypertrophy, and worsening dyskinesia. Furthermore, changes in dopamine receptor (D2R) signaling and fluctuations in dopamine levels in the striatum were found to contribute to VGAT overexpression and the onset of dyskinesia.

Free Research Field

神経化学

Academic Significance and Societal Importance of the Research Achievements

ジスキネジアが発症するメカニズムの一端を発見することができた。また本研究の知見から新たな治療戦略を考案することができる。例えば、VGATを標的した創薬も考案できる。また、LIDやＴＤの診断バイオマーカーとしてGABAが使用できる可能性があり、MRSによるGABA量の計測を提案することができる。新たな治療法や診断法の確立はパーキンソン病患者や統合失調患者への大きな貢献が期待できる。