Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Medical College of Qingdao University, Qingdao, 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Medical College of Qingdao University, Qingdao, 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
Neurochem Int. 2019 May;125:127-135. doi: 10.1016/j.neuint.2019.02.016. Epub 2019 Feb 22.
α-Synuclein plays a central role in synucleinopathies pathogenesis such as Parkinson's disease (PD). Phosphorylation is the most common and important protein modification linked to α-synuclein pathologies. There is mounting evidence suggested iron and α-synuclein are closely related in PD. We previously reported iron up-regulated α-synuclein mRNA levels and induced α-synuclein aggregation. In the present study, we aimed to investigate whether and how phosphorylation was involved in iron-induced α-synuclein regulations. The results showed that iron could induce pS129 α-synuclein (phosphorylation at Ser129) and α-synuclein upregulation in the substantia nigra of iron-overloaded rats and iron-treated SH-SY5Y cells, accompanied by the elevated levels of polo-like kinase 2 (PLK2) and casein kinase 2 (CK2). Over-expression of CK2 or PLK2 induced pS129 α-synuclein up-regulation and inhibitors of CK2 or PLK2 could suppress iron-induced α-synuclein phosphorylation. Antioxidant NAC could fully block iron-induced upregulation of CK2, PLK2 and pS129 α-synuclein levels, indicating oxidative stress plays a critical role in iron-induced α-synuclein phosphorylation. However, iron-induced α-synuclein up-regulation could only be partially blocked by CK2/PLK2 inhibitor or NAC. These findings demonstrate that iron-induced oxidative stress is largely responsible for α-synuclein phosphorylation and upregulation via CK2 and PLK2, and α-synuclein upregulation is not fully phosphorylation-dependent.
α-突触核蛋白在帕金森病（PD）等突触核蛋白病的发病机制中发挥核心作用。磷酸化是与α-突触核蛋白病理最常见和最重要的蛋白修饰。越来越多的证据表明，铁和α-突触核蛋白在 PD 中密切相关。我们之前报道过铁上调α-突触核蛋白 mRNA 水平并诱导α-突触核蛋白聚集。在本研究中，我们旨在研究磷酸化是否以及如何参与铁诱导的α-突触核蛋白调节。结果表明，铁可以诱导铁超载大鼠黑质和铁处理的 SH-SY5Y 细胞中 pS129 α-突触核蛋白（丝氨酸 129 磷酸化）和α-突触核蛋白的上调，同时伴随着 polo 样激酶 2（PLK2）和酪蛋白激酶 2（CK2）水平的升高。CK2 或 PLK2 的过表达诱导 pS129 α-突触核蛋白上调，CK2 或 PLK2 的抑制剂可抑制铁诱导的α-突触核蛋白磷酸化。抗氧化剂 NAC 可完全阻断铁诱导的 CK2、PLK2 和 pS129 α-突触核蛋白水平的上调，表明氧化应激在铁诱导的α-突触核蛋白磷酸化中起关键作用。然而，CK2/PLK2 抑制剂或 NAC 只能部分阻断铁诱导的α-突触核蛋白上调。这些发现表明，铁诱导的氧化应激通过 CK2 和 PLK2 主要负责α-突触核蛋白的磷酸化和上调，并且α-突触核蛋白的上调不完全依赖于磷酸化。
