Center of Parkinson's Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson's Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Department of Neurobiology Capital Medical University, Beijing 100069, China.
Capital Medical University affiliated Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Vessel Disease, The Key Laboratory of Remodeling Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing, 100029, China.
Cell Death Dis. 2017 Sep 21;8(9):e3056. doi: 10.1038/cddis.2017.427.
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by degeneration of dopaminergic neurons in the substantia nigra. α-synuclein (α-syn) and PTEN-induced putative kinase (PINK)1 are two critical proteins associated with the pathogenesis of PD. α-syn induces mitochondrial deficits and apoptosis, PINK1 was found to alleviate α-syn-induced toxicity, but the mechanistic details remain obscure. Here, we show that PINK1 interacts with α-syn mainly in the cytoplasm, where it initiates autophagy. This interaction was dependent on the kinase activity of PINK1 and was abolished by deletion of the kinase domain or a G309D point mutation, an inactivating mutation in the kinase domain. Interaction between PINK1 and α-syn stimulated the removal of excess α-syn, which prevented mitochondrial deficits and apoptosis. Our findings provide evidence for a novel mechanism underlying the protective effects of PINK1 against α-syn-induced neurodegeneration and highlight a novel therapeutic target for PD treatment.
帕金森病（PD）是最常见的神经退行性疾病之一，其特征是黑质中多巴胺能神经元的退化。α-突触核蛋白（α-syn）和 PTEN 诱导的假定激酶 1（PINK1）是与 PD 发病机制相关的两种关键蛋白。α-syn 诱导线粒体缺陷和细胞凋亡，而 PINK1 被发现可以减轻 α-syn 诱导的毒性，但具体的机制仍不清楚。在这里，我们表明 PINK1 主要在细胞质中与 α-syn 相互作用，在细胞质中它启动自噬。这种相互作用依赖于 PINK1 的激酶活性，并且可以通过删除激酶结构域或 G309D 点突变（激酶结构域中的失活突变）来消除。PINK1 与 α-syn 的相互作用刺激了多余的 α-syn 的清除，从而防止了线粒体缺陷和细胞凋亡。我们的发现为 PINK1 对抗 α-syn 诱导的神经退行性变的保护作用提供了新的机制证据，并强调了 PD 治疗的新的治疗靶点。
