The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila.
The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila.
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DOI：
10.1371/journal.pgen.1001229
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发表时间：
2010-12-02
期刊：
影响因子：
4.5
通讯作者：
Takahashi R
中科院分区：
文献类型：
--
作者：
Imai Y;Kanao T;Sawada T;Kobayashi Y;Moriwaki Y;Ishida Y;Takeda K;Ichijo H;Lu B;Takahashi R
pten诱导的激酶1 （PINK1）是线粒体稳态所必需的，是早发性帕金森病（PD）的基因产物。另一个早发性PD基因产物Parkin在果蝇的遗传研究中被认为在PINK1信号通路的下游起作用。PINK1是一种丝氨酸/苏氨酸激酶，具有可预测的线粒体靶序列和n端可能的跨膜结构域，而Parkin是一种具有泛素连接酶（E3）活性的无名指蛋白。然而，PINK1和Parkin如何调节线粒体活性在很大程度上是未知的。为了探索PINK1和Parkin相互作用的分子机制，我们从人培养细胞中生化纯化PINK1结合蛋白，并利用果蝇PINK1 （dPINK1）模型筛选编码这些结合蛋白的基因，分离出参与PINK1病理的分子。在这里，我们报道了PINK1结合的线粒体蛋白PGAM5调节PINK1通路。果蝇PGAM5 （dPGAM5）的缺失可以抑制由dPINK1失活导致的肌肉变性、运动缺陷和较短的寿命，这些可归因于线粒体变性。然而，dPGAM5失活不能调节帕金突变果蝇的表型。相反，dPGAM5的异位表达加重了dPINK1和果蝇parkin （dParkin）表型。这些结果表明，PGAM5负调控与线粒体维持相关的PINK1通路，此外，PGAM5在PINK1和Parkin之间起作用，或独立于PINK1下游的Parkin起作用。帕金森病（PD）是一种以中脑多巴胺能（DA）神经元变性为病理特征的神经退行性疾病。一小部分PD病例以孟德尔方式遗传，并且已经确定了几种致病基因。PINK1和Parkin基因是早发性帕金森病常染色体隐性基因。出乎意料的是，在果蝇中，PINK1或Parkin的功能丧失会导致飞行肌的线粒体变性，这表现出明显的异常翅膀姿势表型，从而允许快速的遗传筛选。我们从人培养细胞中纯化了PINK1结合蛋白，并利用PINK1突变体果蝇筛选了这些结合蛋白的基因。我们发现PINK1结合蛋白磷酸甘油酸突变酶5 （PGAM5）失活可抑制PINK1活性丧失引起的线粒体变性。虽然在果蝇中，parkin被认为是PINK1的遗传下游，但PGAM5的缺失未能通过parkin失活来调节表型。我们的发现表明，对于高能量需求组织（如肌肉和DA神经元）的线粒体维持，PGAM5在PINK1和Parkin之间起作用，或者独立于PINK1下游的Parkin发挥作用。
PTEN-induced kinase 1 (PINK1), which is required for mitochondrial homeostasis, is a gene product responsible for early-onset Parkinson's disease (PD). Another early onset PD gene product, Parkin, has been suggested to function downstream of the PINK1 signalling pathway based on genetic studies in Drosophila. PINK1 is a serine/threonine kinase with a predicted mitochondrial target sequence and a probable transmembrane domain at the N-terminus, while Parkin is a RING-finger protein with ubiquitin-ligase (E3) activity. However, how PINK1 and Parkin regulate mitochondrial activity is largely unknown. To explore the molecular mechanism underlying the interaction between PINK1 and Parkin, we biochemically purified PINK1-binding proteins from human cultured cells and screened the genes encoding these binding proteins using Drosophila PINK1 (dPINK1) models to isolate a molecule(s) involved in the PINK1 pathology. Here we report that a PINK1-binding mitochondrial protein, PGAM5, modulates the PINK1 pathway. Loss of Drosophila PGAM5 (dPGAM5) can suppress the muscle degeneration, motor defects, and shorter lifespan that result from dPINK1 inactivation and that can be attributed to mitochondrial degeneration. However, dPGAM5 inactivation fails to modulate the phenotypes of parkin mutant flies. Conversely, ectopic expression of dPGAM5 exacerbated the dPINK1 and Drosophila parkin (dParkin) phenotypes. These results suggest that PGAM5 negatively regulates the PINK1 pathway related to maintenance of the mitochondria and, furthermore, that PGAM5 acts between PINK1 and Parkin, or functions independently of Parkin downstream of PINK1. Parkinson's disease (PD) is a neurodegenerative disease pathologically characterized by degeneration of dopaminergic (DA) neurons in the midbrain. A small percentage of PD cases are inherited in a Mendelian manner, and several disease-causing genes have been identified. The PINK1 and Parkin genes have been isolated as the genes for autosomal recessive form of early-onset PD. Unexpectedly, loss of function of either PINK1 or Parkin in Drosophila causes mitochondrial degeneration in the flight muscles, which exhibits a visible phenotype of abnormal wing postures, allowing a rapid genetic screening. We purified PINK1-binding proteins from human cultured cells and screened the gene for these binding proteins using the PINK1 mutant flies. We found that inactivation of a PINK1-binding protein phosphoglycerate mutase 5 (PGAM5) suppresses mitochondrial degeneration caused by the loss of PINK1 activity. Although parkin is suggested to be genetically downstream of PINK1 in Drosophila, loss of PGAM5 failed to modulate the phenotypes by parkin inactivation. Our finding suggested that, for mitochondrial maintenance of tissues with high-energy demands such as the muscles and DA neurons, PGAM5 acts between PINK1 and Parkin, or functions independently of Parkin downstream of PINK1.
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DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K
影响因子：
4.7
作者：
Lin W;Kang UJ
通讯作者：
Kang UJ
影响因子：
7
作者：
Kinoshita, E;Kinoshita-Kikuta, E;Koike, T
通讯作者：
Koike, T
影响因子：
11.4
作者：
Imai, Yuzuru;Gehrke, Stephan;Lu, Bingwei
通讯作者：
Lu, Bingwei
影响因子：
64.8
作者：
Clark, Ira E.;Dodson, Mark W.;Guo, Ming
通讯作者：
Guo, Ming