Bioenergetic consequences of PINK1 mutations in Parkinson disease.
Bioenergetic consequences of PINK1 mutations in Parkinson disease.
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DOI：
10.1371/journal.pone.0025622
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Schapira AH
中科院分区：
文献类型：
--
作者：
Abramov AY;Gegg M;Grunewald A;Wood NW;Klein C;Schapira AH
PTEN诱导的蛋白激酶1(PINK1)基因突变是家族性帕金森病(PD)的原因之一。PINK1蛋白定位于线粒体，PINK1基因敲除模型显示线粒体功能异常。本研究的目的是确定来自具有一系列PINK1突变的PD患者的细胞是否表现出类似的线粒体功能缺陷，异常的性质和严重程度是否因突变而异，并与临床特征相关。我们用单细胞技术研究了PINK1突变患者的活成纤维细胞中的线粒体生物能量学。我们发现PINK1突变患者的成纤维细胞存在显著的生物能量学缺陷，包括线粒体膜电位降低，氧化还原状态改变，由底物可获得性决定的呼吸缺陷，以及对钙刺激的敏感性增强和相关的线粒体通透性开孔。突变细胞产生自由基的基础速率增加。不同突变的异常模式和严重程度不同，这些细胞中不太严重的缺陷与帕金森病发病年龄较晚有关。这些结果为帕金森病中PINK1突变的分子病理学提供了洞察，也证实了底物可用性在决定生化表型中的关键作用-从而为绕过这些异常的新的治疗策略提供了可能性。
Mutations of the gene for PTEN-induced kinase 1 (PINK1) are a cause of familial Parkinson's disease (PD). PINK1 protein has been localised to mitochondria and PINK1 gene knockout models exhibit abnormal mitochondrial function. The purpose of this study was to determine whether cells derived from PD patients with a range of PINK1 mutations demonstrate similar defects of mitochondrial function, whether the nature and severity of the abnormalities vary between mutations and correlate with clinical features. We investigated mitochondrial bioenergetics in live fibroblasts from PINK1 mutation patients using single cell techniques. We found that fibroblasts from PINK1 mutation patients had significant defects of bioenergetics including reduced mitochondrial membrane potential, altered redox state, a respiratory deficiency that was determined by substrate availability, and enhanced sensitivity to calcium stimulation and associated mitochondrial permeability pore opening. There was an increase in the basal rate of free radical production in the mutant cells. The pattern and severity of abnormality varied between different mutations, and the less severe defects in these cells were associated with later age of onset of PD. The results provide insight into the molecular pathology of PINK1 mutations in PD and also confirm the critical role of substrate availability in determining the biochemical phenotype – thereby offering the potential for novel therapeutic strategies to circumvent these abnormalities.
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DOI：
10.1073/pnas.0913485107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Ziviani, Elena;Tao, Ran N.;Whitworth, Alexander J.
通讯作者：
Whitworth, Alexander J.
影响因子：
3.5
作者：
Gegg, Matthew E.;Cooper, J. Mark;Taanman, Jan-Willem
通讯作者：
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DOI：
10.1073/pnas.0711845105
发表时间：
2008-05-13
影响因子：
11.1
作者：
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通讯作者：
Lu, Bingwei
影响因子：
4.4
作者：
Piccoli, Claudia;Sardanelli, Annamaria;Papa, Sergio
通讯作者：
Papa, Sergio
影响因子：
64.8
作者：
Clark, Ira E.;Dodson, Mark W.;Guo, Ming
通讯作者：
Guo, Ming