TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.
TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.
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DOI：
10.1016/j.neuron.2021.09.031
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发表时间：
2021-12-01
期刊：
影响因子：
16.2
通讯作者：
Ko HS
中科院分区：
文献类型：
--
作者：
Seo BA;Kim D;Hwang H;Kim MS;Ma SX;Kwon SH;Kweon SH;Wang H;Yoo JM;Choi S;Kwon SH;Kang SU;Kam TI;Kim K;Karuppagounder SS;Kang BG;Lee S;Park H;Kim S;Yan W;Li YS;Kuo SH;Redding-Ochoa J;Pletnikova O;Troncoso JC;Lee G;Mao X;Dawson VL;Dawson TM;Ko HS
葡糖脑苷脂酶（GCase）的损伤与帕金森病（PD）的发展密切相关，但负责其损伤的调节剂仍然难以捉摸。在本文中，我们确定了E3连接酶甲状腺激素受体相互作用蛋白12（TRIP 12）作为GCase的关键调节因子。TRIP 12与GCase相互作用并在赖氨酸293处泛素化GCase以通过泛素蛋白酶体降解来控制其降解。TRIP 12泛素化的GCase通过过早降解和随后的α-突触核蛋白积累导致其功能受损。TRIP 12过表达导致线粒体功能障碍，其通过GCase过表达而改善。此外，条件性TRIP 12体外敲除和体内敲低促进GCase的表达，其阻断α-突触核蛋白预形成的纤维（α-syn PFF）引起的多巴胺能神经变性。此外，TRIP 12在人PD脑和基于α-突触核蛋白的小鼠模型中积累。TRIP 12作为GCase调节因子的鉴定为PD中功能失调的GCase驱动的神经变性的分子机制提供了新的视角。E3连接酶TRIP 12与PD发展相关的GCase相互作用并泛素化。TRIP 12泛素化的GCase导致其功能受损，以及随后的α-突触核蛋白积累和线粒体功能障碍。TRIP 12耗竭促进GCase的表达，GCase阻断由于α-突触核蛋白预形成的原纤维引起的多巴胺能神经变性。
Impairment in glucocerebrosidase (GCase) is strongly associated with the development of Parkinson’s disease (PD), yet the regulators responsible for its impairment remain elusive. In this paper, we identify the E3 ligase Thyroid Hormone Receptor Interacting Protein 12 (TRIP12) as a key regulator of GCase. TRIP12 interacts with and ubiquitinates GCase at lysine 293 to control its degradation via ubiquitin proteasomal degradation. Ubiquitinated GCase by TRIP12 leads to its functional impairment through premature degradation, and subsequent accumulation of α-synuclein. TRIP12 overexpression causes mitochondrial dysfunction, which is ameliorated by GCase overexpression. Further, conditional TRIP12 knockout in vitro and knockdown in vivo promotes the expression of GCase, which blocks α-synuclein preformed fibrils (α-syn PFFs)-provoked dopaminergic neurodegeneration. Moreover, TRIP12 accumulates in human PD brain and α-synuclein based mouse models. The identification of TRIP12 as a regulator of GCase provides a new perspective on the molecular mechanisms underlying dysfunctional GCase-driven neurodegeneration in PD. The E3 ligase TRIP12 interacts with and ubiquitinates GCase associated with the development of PD. The ubiquitinated GCase by TRIP12 leads to its functional impairment, and subsequent accumulation of α-synuclein and mitochondrial dysfunction. TRIP12 depletion promotes the expression of GCase, which blocks dopaminergic neurodegeneration due to α-synuclein preformed fibrils.
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影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
6.1
作者：
Gegg ME;Schapira AH
通讯作者：
Schapira AH
DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
4.8
作者：
Lee, HJ;Shin, SY;Lee, SJ
通讯作者：
Lee, SJ
影响因子：
64.5
作者：
Gudjonsson, Thorkell;Altmeyer, Matthias;Lukas, Claudia
通讯作者：
Lukas, Claudia