Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction.
Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction.
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DOI：
10.1111/j.1471-4159.2012.07734.x
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发表时间：
2012-06
影响因子：
4.7
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Wang X;Petrie TG;Liu Y;Liu J;Fujioka H;Zhu X
Mitochondrial dysfunction represents a critical event during the pathogenesis of Parkinson’s disease (PD) and expanding evidences demonstrate that an altered balance in mitochondrial fission/fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction/degeneration. In this study, we investigated whether DJ-1 is involved in the regulation of mitochondrial dynamics and function in neuronal cells. Confocal and electron microscopic analysis demonstrated that M17 human neuroblastoma cells over-expressing wild-type DJ-1 (WT DJ-1 cells) displayed elongated mitochondria while M17 cells over-expressing PD-associated DJ-1 mutants (R98Q, D149A and L166P) (mutant DJ-1 cells) showed significant increase of fragmented mitochondria. Similar mitochondrial fragmentation was also noted in primary hippocampal neurons overexpressing PD-associated mutant forms of DJ-1. Functional analysis revealed that over-expression of PD-associated DJ- 1 mutants resulted in mitochondria dysfunction and increased neuronal vulnerability to oxidative stress (H2O2) or neurotoxin. Further immunoblot studies demonstrated that levels of dynamin-like protein (DLP1), also known as Drp1, a regulator of mitochondrial fission, was significantly decreased in WT DJ-1 cells but increased in mutant DJ-1 cells. Importantly, DLP1 knockdown in these mutant DJ-1 cells rescued the abnormal mitochondria morphology and all associated mitochondria/neuronal dysfunction. Taken together, these studies suggest that DJ-1 is involved in the regulation of mitochondrial dynamics through modulation of DLP1 expression and PD-associated DJ-1 mutations may cause PD by impairing mitochondrial dynamics and function.
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影响因子：
10.7
作者：
Lucas, J. Ignasi;Marin, Ignacio
通讯作者：
Marin, Ignacio
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
11.4
作者：
Barsoum, Mark J.;Yuan, Hua;Bossy-Wetzel, Ella
通讯作者：
Bossy-Wetzel, Ella
影响因子：
8.6
作者：
Cookson, Mark R.
通讯作者：
Cookson, Mark R.
DOI：
10.1073/pnas.0711647105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Li, Hongmei;Chen, Yingbei;Jonas, Elizabeth A.
通讯作者：
Jonas, Elizabeth A.