Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation
Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation
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DOI：
10.1172/jci39088
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发表时间：
2009-11-01
影响因子：
15.9
通讯作者：
Feany, Mel B.
中科院分区：
文献类型：
--
作者：
Chen, Li;Periquet, Magali;Feany, Mel B.
神经元蛋白-突触核蛋白突变导致家族性帕金森病。α -突触核蛋白丝氨酸129的磷酸化在帕金森病中很突出，并影响α -突触核蛋白的神经毒性。在这里，我们报道了α -突触核蛋白在表达野生型人α -突触核蛋白的转基因果蝇中酪氨酸125位点也被磷酸化，并且这种酪氨酸磷酸化保护了帕金森病果蝇模型中α -突触核蛋白的神经毒性。Western blot分析显示，在丝氨酸129位点磷酸化可增加α -突触核蛋白可溶性寡聚物的含量，而在酪氨酸125位点磷酸化可降低α -突触核蛋白可溶性寡聚物的含量。在人类和果蝇的正常衰老过程中，酪氨酸125磷酸化减少。值得注意的是，帕金森病相关突触核蛋白性痴呆伴路易体患者的皮质组织显示酪氨酸125磷酸化较少。我们的研究结果表明，帕金森氏病和相关的突触核蛋白病中的α -突触核蛋白神经毒性可能是由于丝氨酸129磷酸化的有害低聚物促进作用与酪氨酸125磷酸化抑制毒性低聚物形成的神经保护作用之间的不平衡。
Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wildtype human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.