Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain mutant.
Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain mutant.
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DOI：
10.1093/hmg/ddq428
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发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Cheetham ME
中科院分区：
文献类型：
--
作者：
Rose JM;Novoselov SS;Robinson PA;Cheetham ME
线粒体功能障碍是许多神经退行性疾病的特征。帕金森病相关的泛素蛋白连接酶，帕金，是重要的消除受损的线粒体自噬（mitophagy）在一个多步骤的过程。在这里，我们表明，帕金环结构域突变体（C289 G）未能重新分配到受损的线粒体，不能诱导线粒体自噬处理后的线粒体解偶联剂羰基氰间甲基腙，因为蛋白质的错误折叠和聚集。Parkin（C289 G）聚集和包涵体形成被神经元DnaJ/Hsp 40伴侣蛋白HSJ 1a（DNAJB 2a）抑制。重要的是，HSJ 1a和DNAJB 6还通过促进Parkin（C289 G）和自噬标志物LC 3重新定位到去极化线粒体来恢复线粒体自噬。Parkin活性的拯救和聚集的抑制是HSJ 1a的J结构域依赖性的，表明Hsp 70参与这些过程，但不依赖于HSJ 1a泛素相互作用基序。HSJ 1a的表达没有增强野生型帕金介导的线粒体自噬。这些数据显示了分子伴侣介导帕金错误折叠突变体的功能恢复和对抗帕金森病中与帕金聚集相关的缺陷的潜力。
Mitochondrial dysfunction is characteristic of many neurodegenerative diseases. The Parkinson's disease-associated ubiquitin–protein ligase, Parkin, is important in the elimination of damaged mitochondria by autophagy (mitophagy) in a multistep process. Here, we show that a Parkin RING domain mutant (C289G) fails to redistribute to damaged mitochondria and cannot induce mitophagy after treatment with the mitochondrial uncoupler carbonyl cyanide m-methylhydrazone, because of protein misfolding and aggregation. Parkin(C289G) aggregation and inclusion formation were suppressed by the neuronal DnaJ/Hsp40 chaperone HSJ1a(DNAJB2a). Importantly, HSJ1a and DNAJB6 also restored mitophagy by promoting the relocation of Parkin(C289G) and the autophagy marker LC3 to depolarized mitochondria. The rescue of Parkin activity and suppression of aggregation were J domain dependent for HSJ1a, suggesting the involvement of Hsp70 in these processes, but were not dependent on the HSJ1a ubiquitin interaction motif. HSJ1a expression did not enhance mitophagy mediated by wild-type Parkin. These data show the potential of molecular chaperones to mediate the functional recovery of Parkin misfolding mutants and to combat deficits associated with Parkin aggregation in Parkinson's disease.
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影响因子：
4.7
作者：
LaVoie, Matthew J.;Cortese, Giuseppe P.;Schlossmacher, Michael G.
通讯作者：
Schlossmacher, Michael G.
影响因子：
3.5
作者：
Cookson, MR;Lockhart, PJ;Farrer, MJ
通讯作者：
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Cheetham, ME
影响因子：
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作者：
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通讯作者：
Kampinga, Harm H.
影响因子：
3.3
作者：
Ardley, HC;Scott, GB;Robinson, PA
通讯作者：
Robinson, PA