| Project/Area Number |
26461263
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
Nagai Yoshitaka 大阪大学, 大学院医学系研究科, 教授 (60335354)
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| Research Collaborator |
Sugeno Naoto 東北大学, 大学病院, 助教 (30509550)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | パーキンソン病 / PARK17 / VPS35 / レトロマー / エンドソーム / カテプシンD / アルファシヌクレイン / ショウジョウバエモデル / メンブレントラフィック / DNAJC13 / αシヌクレイン / アクチン / 神経変性 / 神経変性疾患 / プリオン仮説 / 小胞輸送 / ESCRT / 異常タンパク凝集 / コンディショナルノックアウトマウス / 異常蛋白伝播 / 多系統萎縮症 / シヌクレイノパチー |
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| Outline of Final Research Achievements |
In this study, we first showed that the silencing of VPS35 in cultured cells caused a reduction in the distribution of CI-MPR and impaired the maturation of CTSD. Second, we found that the amount of pro-CTSD was substantially increased not only in the culture medium of the VPS35-deficient cells but also in the CSF from sporadic PD patients. Third, we demonstrated that silencing VPS35 impairs the maturation of CTSD, which occurs concomitant with a striking accumulation of αSYN in lysosomes. Finally, we showed that the RNAi-mediated silencing of dVPS35 not only induced the accumulation of the insoluble αSYN species in the brain but also exacerbated mild eye disorganization, as well as locomotor impairment in the flies expressing the human wt-αSYN. Cumulatively, these data suggest that the retromer-dependent sorting machinery plays a role in αSYN catabolism by modulating the intracellular processing and activation of CTSD and might thereby contribute to the pathogenesis of PD.
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