Laboratory of Molecular and Chemical Biology of Neurodegeneration and Neurodegenerative Disease Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):E3945-54. doi: 10.1073/pnas.1309991110. Epub 2013 Aug 27.
An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies.
由于基因重复/三重复或降解受损导致α-突触核蛋白水平升高足以引发其聚集并导致家族性帕金森病 (PD)。因此，降低α-突触核蛋白水平代表了治疗 PD 和相关突触核蛋白病的可行治疗策略。在这里，我们报告说，丝氨酸/苏氨酸激酶 Polo-like 激酶 2 (PLK2)，一种在突触核蛋白病大脑中上调的酶，以激酶活性依赖性方式与α-突触核蛋白相互作用、磷酸化并增强α-突触核蛋白自噬降解。PLK2 介导的α-突触核蛋白降解需要 S129 的磷酸化和 PLK2/α-突触核蛋白复合物的形成。在 PD 的大鼠遗传模型中，PLK2 的过表达减少了神经元内人α-突触核蛋白的积累，抑制了多巴胺能神经退行性变，并逆转了α-突触核蛋白过表达诱导的偏侧帕金森运动障碍。这种 PLK2 介导的神经保护作用也依赖于 PLK2 活性和α-突触核蛋白磷酸化。总之，我们的研究结果表明，PLK2 是以前未描述的α-突触核蛋白周转调节剂，调节其激酶活性可能是治疗突触核蛋白病的可行靶点。
