Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP
Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP
复制标题
DOI：
10.1073/pnas.0705363105
复制
发表时间：
2008-02-05
影响因子：
11.1
通讯作者：
Park, David S.
中科院分区：
文献类型：
--
作者：
Haque, M. Emdadul;Thomas, Kelly J.;Park, David S.
PTEN诱导的推定激酶1（Pink 1）是最近发现的与家族性帕金森病（PD）的隐性形式相关的基因。该激酶含有线粒体定位序列，据报道至少部分存在于线粒体中。然而，Pink 1的丢失导致多巴胺神经元丢失的方式及其对线粒体功能的影响以及与死亡的相关性都不清楚。在这里，我们报告说，通过RNAi耗尽Pink 1增加MPP+诱导的神经元毒性。此外，野生型Pink 1，而不是与家族性PD相关的G309 D突变体或工程化激酶死亡突变体K219 M，在体外和体内都能保护神经元免受MPTP的侵害。有趣的是，一个突变体，含有一个删除的推定的细胞靶向基序被靶向细胞质，但仍然提供保护1-甲基-4-苯基吡啶（MPP+）/1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的毒性。此外，我们还表明，内源性Pink 1是本地化的细胞溶质以及线粒体组分。因此，我们的研究结果表明，Pink 1在神经元的存活中起着功能性作用，并且除了其在线粒体中的其他作用外，细胞质靶点可能对这种保护作用很重要。
PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP+. Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both in vitro and in vivo. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.