Inglis Kelly J, Chereau David, Brigham Elizabeth F, Chiou San-San, Schöbel Susanne, Frigon Normand L, Yu Mei, Caccavello Russell J, Nelson Seth, Motter Ruth, Wright Sarah, Chian David, Santiago Pamela, Soriano Ferdie, Ramos Carla, Powell Kyle, Goldstein Jason M, Babcock Michael, Yednock Ted, Bard Frederique, Basi Guriqbal S, Sham Hing, Chilcote Tamie J, McConlogue Lisa, Griswold-Prenner Irene, Anderson John P
Elan Pharmaceuticals, South San Francisco, California 94080.
Elan Pharmaceuticals, South San Francisco, California 94080.
J Biol Chem. 2009 Jan 30;284(5):2598-2602. doi: 10.1074/jbc.C800206200. Epub 2008 Nov 12.
Several neurological diseases, including Parkinson disease and dementia with Lewy bodies, are characterized by the accumulation of alpha-synuclein phosphorylated at Ser-129 (p-Ser-129). The kinase or kinases responsible for this phosphorylation have been the subject of intense investigation. Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons. PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay. Inhibitors of PLK kinases inhibited alpha-synuclein phosphorylation both in primary cortical cell cultures and in mouse brain in vivo. Finally, specific knockdown of PLK2 expression by transduction with short hairpin RNA constructs or by knock-out of the plk2 gene reduced p-Ser-129 levels. These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system.
包括帕金森病和路易体痴呆在内的几种神经疾病，其特征是在丝氨酸129（p-Ser-129）位点磷酸化的α-突触核蛋白的积累。负责这种磷酸化的一种或多种激酶一直是深入研究的对象。在此，我们提供证据表明，polo样激酶2（PLK2，也称为血清诱导激酶或SNK）是神经元中α-突触核蛋白在丝氨酸129位点磷酸化的主要促成因素。在体外生化测定中，PLK2直接在丝氨酸129位点磷酸化α-突触核蛋白。PLK激酶抑制剂在原代皮质细胞培养物和体内小鼠脑中均抑制α-突触核蛋白的磷酸化。最后，通过短发夹RNA构建体转导或敲除plk2基因特异性敲低PLK2表达降低了p-Ser-129水平。这些结果表明，PLK2在中枢神经系统中α-突触核蛋白的磷酸化中起关键作用。
