Pathogenic mechanisms of Parkinson's disease and movement disorders medicated by excess zinc influx into dopaminergic neuron and its rescue

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08312
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: University of Shizuoka
• Principal Investigator: Tamano Haruna 静岡県立大学, 薬学部, 特任講師 (30322697)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: パーキンソン病 / 黒質 / 細胞外亜鉛 / 亜鉛毒性 / 活性酸素 / ドパミン作動性神経 / グルタミン酸興奮毒性

Outline of Final Research Achievements

Parkinson's disease (PD) is characterized by a selective loss of dopaminergic neurons in the substantia nigra in the brain. This study demonstrates a unique mechanism of nigral dopaminergic degeneration, in which rapid intracellular Zn2+dysregulation via reactive oxygen species (ROS) production causes PD in rats, which is induced by paraquart (PQ) and 6-hydroxydopamine (6-OHDA). ROS produced with PQ and 6-OHDA, which is retrogradely transported to presynaptic glutamatergic neuron terminals, activate TRPM2 cation channels and increase glutamate release, resulting in intracellular Zn2+ dysregulation in postsynaptic nigral dopaminergic neurons via rapid extracellular Zn2+ influx via AMPA receptor activation.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

活性酸素産生物質によって誘発されるパーキンソン病モデル動物を用いた本研究から、脳黒質ドパミンニューロン変性のメカニズムには、活性酸素によって誘導される黒質細胞外亜鉛の速やかな過剰流入による細胞内亜鉛毒性が重要であること、この亜鉛毒性を阻止することはパーキンソン病の予防・阻止につかながることが示された。