The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy

被引：246

作者：

Burchell, Victoria S. ^{[1
]}

Nelson, David E. ^{[2
]}

Sanchez-Martinez, Alvaro ^{[3
,4
]}

Delgado-Camprubi, Marta ^{[1
]}

Ivatt, Rachael M. ^{[3
,4
]}

Pogson, Joe H. ^{[3
,4
]}

Randle, Suzanne J. ^{[2
]}

Wray, Selina ^{[1
]}

Lewis, Patrick A. ^{[1
]}

Houlden, Henry ^{[1
]}

Abramov, Andrey Y. ^{[1
]}

Hardy, John ^{[1
]}

Wood, Nicholas W. ^{[1
]}

Whitworth, Alexander J. ^{[3
,4
]}

Laman, Heike ^{[2
]}

Plun-Favreau, Helene ^{[1
]}

机构：

[1] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[2] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England

[3] Ctr Dev & Biomed Genet, MRC, Sheffield, S Yorkshire, England

[4] Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England

来源：

NATURE NEUROSCIENCE | 2013年 / 16卷 / 09期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会; 欧洲研究理事会;

关键词：

F-BOX PROTEIN; MITOCHONDRIAL PATHOLOGY; PINK1; PROTEASOME; COMPLEX; DROSOPHILA-PINK1; DEGENERATION; INDUCTION; APOPTOSIS; PROMOTES;

D O I：

10.1038/nn.3489

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Compelling evidence indicates that two autosomal recessive Parkinson's disease genes, PINK1 (PARK6) and Parkin (PARK2), cooperate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain-containing protein Fbxo7 (encoded by PARK15) also cause early-onset autosomal recessive Parkinson's disease, by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting a functional relationship between the two proteins. Parkinson's disease-causing mutations in Fbxo7 interfered with this process, emphasizing the importance of mitochondrial dysfunction in Parkinson's disease pathogenesis.

引用

页码：1257 / U135

页数：11

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