α-突触核蛋白通过抑制 Polo 样激酶 Cdc5/Plk2 破坏应激信号。
α-Synuclein disrupts stress signaling by inhibiting polo-like kinase Cdc5/Plk2.
机构信息
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
出版信息
Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16119-24. doi: 10.1073/pnas.1206286109. Epub 2012 Sep 17.
Abstract
Parkinson disease (PD) results from the slow, progressive loss of dopaminergic neurons in the substantia nigra. Alterations in α-synuclein (aSyn), such as mutations or multiplications of the gene, are thought to trigger this degeneration. Here, we show that aSyn disrupts mitogen-activated protein kinase (MAPK)-controlled stress signaling in yeast and human cells, which results in inefficient cell protective responses and cell death. aSyn is a substrate of the yeast (and human) polo-like kinase Cdc5 (Plk2), and elevated levels of aSyn prevent Cdc5 from maintaining a normal level of GTP-bound Rho1, which is an essential GTPase that regulates stress signaling. The nine N-terminal amino acids of aSyn are essential for the interaction with polo-like kinases. The results support a unique mechanism of PD pathology.
摘要
帕金森病（PD）是由黑质中多巴胺能神经元的缓慢、进行性丧失引起的。α-突触核蛋白（aSyn）的改变，如基因突变或基因倍增，被认为是引发这种退化的原因。在这里，我们表明 aSyn 破坏了丝裂原活化蛋白激酶（MAPK）控制的酵母和人类细胞中的应激信号转导，导致细胞保护性反应和细胞死亡效率低下。aSyn 是酵母（和人类）类 polo 样激酶 Cdc5（Plk2）的底物，而升高的 aSyn 水平阻止 Cdc5 维持正常水平的 GTP 结合 Rho1，Rho1 是一种调节应激信号转导的必需 GTP 酶。aSyn 的九个 N 端氨基酸对于与 polo 样激酶的相互作用至关重要。这些结果支持 PD 病理学的独特机制。
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