Pathophysiological roles of convulsive neurological disease-causing gene PRRT2 in the synapse
| Project/Area Number |
18H02720
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | Nagasaki University |
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Principal Investigator |
IWATA Nobuhisa 長崎大学, 医歯薬学総合研究科(薬学系), 教授 (70246213)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
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| Keywords | ジスキネジア / PRRT2 / 大脳基底核 / ドパミン / ドパミントランスポーター / シナプス / マイクロダイアリシス / カルパイン / ノックインマウス / けいれん / 痙攣 / ディスキネジア |
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| Outline of Final Research Achievements |
Mutations in proline-rich transmembrane protein 2 (PRRT2) are associated with several paroxysmal neurological diseases represented by paroxysmal kinesigenic dyskinesia (PKD), but physiological functions of PRRT2 and pathogenic mechanisms remain largely unclear as well as the causative brain regions and neuronal circuits. Here we generated Prrt2 knock-in (KI) mice harboring the most frequent PKD-related Prrt2 mutation and the mice showed that the Prrt2 mutation leads to an excessive activity-dependent dopaminergic transmission in striatum. Moreover, we found that PRRT2 regulates a dopamine transporter (DAT) activity in cultured neuroblastoma overexpressing both genes. Therefore, we considered that PRRT2 may contribute release and/or uptake of dopamine in the striatum and that loss of function of PRRT2 might cause PKD. Our findings showed that dopaminergic neurons in the basal ganglia could be a novel target for a treatment of PKD and several other neurological diseases with dyskinesia.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、PRRT2の機能低下による線条体ドパミン伝達の異常がPKD発症に関連することを明らかにした。PRRT2はPKDの他、てんかんや片頭痛等の様々な神経疾患にも関連するため、これらの疾患に対する新たな医薬品創出につながる可能性がある。また、これまで未知であったPRRT2のシナプス機能を解明したことにより、シナプス伝達が調節される仕組みの学術的理解をより発展させられたと考えている。
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Report
(4 results)
Research Products
(16 results)
