VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.
VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.
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DOI：
10.1016/j.neuron.2013.02.029
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发表时间：
2013-04-10
期刊：
影响因子：
16.2
通讯作者：
Taylor JP
中科院分区：
文献类型：
--
作者：
Kim NC;Tresse E;Kolaitis RM;Molliex A;Thomas RE;Alami NH;Wang B;Joshi A;Smith RB;Ritson GP;Winborn BJ;Moore J;Lee JY;Yao TP;Pallanck L;Kundu M;Taylor JP
VCP的突变引起多系统变性，影响神经系统、肌肉和/或骨骼。患者可能会出现ALS、帕金森症、额颞叶痴呆、肌病、佩吉特病或这些疾病的组合。发病机制尚不清楚。我们建立了VCP突变依赖性变性果蝇模型。表型与PINK1和帕金突变体相似，包括明显的线粒体缺陷。事实上，VCP在体内与PINK1/parkin通路发生遗传相互作用。矛盾的是，VCP可以补充PINK1缺乏症，但不能补充parkin缺乏症。体外机制研究解决了这一悖论的基础，表明VCP募集到受损线粒体需要帕金森介导的线粒体靶点泛素化。VCP的募集与线粒体分裂的时间一致，并且VCP是体外和体内蛋白酶体依赖性Mitofusins降解所必需的。此外，VCP及其接头Npl4/Ufd1是通过PINK1/Parkin途径清除受损线粒体所必需的，而VCP的致病性突变会损害这一功能。
Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget’s disease or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration. The phenotype is reminiscent of PINK1 and parkin mutants, including a pronounced mitochondrial defect. Indeed, VCP interacts genetically with the PINK1/parkin pathway in vivo. Paradoxically, VCP complements PINK1 deficiency but not parkin deficiency. The basis of this paradox is resolved by mechanistic studies in vitro showing that VCP recruitment to damaged mitochondria requires Parkin-mediated ubiquitination of mitochondrial targets. VCP recruitment coincides temporally with mitochondrial fission, and VCP is required for proteasome-dependent degradation of Mitofusins in vitro and in vivo. Further, VCP and its adaptor Npl4/Ufd1 are required for clearance of damaged mitochondria via the PINK1/Parkin pathway, and this is impaired by pathogenic mutations in VCP.
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影响因子：
11.4
作者：
Braun, S;Matuschewski, K;Jentsch, S
通讯作者：
Jentsch, S
影响因子：
3.3
作者：
Dalal, S;Rosser, MFN;Hanson, PI
通讯作者：
Hanson, PI
DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
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作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K
DOI：
10.1083/jcb.200809125
发表时间：
2008-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Narendra D;Tanaka A;Suen DF;Youle RJ
通讯作者：
Youle RJ
影响因子：
3.5
作者：
Gegg, Matthew E.;Cooper, J. Mark;Taanman, Jan-Willem
通讯作者：
Taanman, Jan-Willem