Biology Department, Lake Forest College, Box P7, 555 North Sheridan Road, Lake Forest, IL 60045, USA.
Parkinsons Dis. 2011;2011:392180. doi: 10.4061/2011/392180. Epub 2011 Jul 3.
In Parkinson's disease (PD), misfolded and aggregated α-synuclein protein accumulates in degenerating midbrain dopaminergic neurons. The amino acid alanine-76 in α-synuclein and phosphorylation at serine-87 and serine-129 are thought to regulate its aggregation and toxicity. However, their exact contributions to α-synuclein membrane association are less clear. We found that α-synuclein is indeed phosphorylated in fission yeast and budding yeast, the two models that we employed for assessing α-synuclein aggregation and membrane association properties, respectively. Surprisingly, blocking serine phosphorylation (S87A, S129A, and S87A/S129A) or mimicking it (S87D, S129D) altered α-synuclein aggregation in fission yeast. Either blocking or mimicking this phosphorylation increased endomembrane association in fission yeast, but only mimicking it decreased plasma membrane association in budding yeast. Polar substitution mutations of alanine-76 (A76E and A76R) decreased α-synuclein membrane association in budding yeast and decreased aggregation in fission yeast. These yeast studies extend our understanding of serine phosphorylation and alanine-76 contributions to α-synuclein aggregation and are the first to detail their impact on α-synuclein's plasma membrane and endomembrane association.
在帕金森病 (PD) 中，错误折叠和聚集的α-突触核蛋白在退化的中脑多巴胺能神经元中积累。α-突触核蛋白中的氨基酸丙氨酸-76 和丝氨酸-87 和丝氨酸-129 的磷酸化被认为调节其聚集和毒性。然而，它们对α-突触核蛋白膜结合的确切贡献尚不清楚。我们发现α-突触核蛋白在裂殖酵母和芽殖酵母中确实被磷酸化，这两种模型分别用于评估α-突触核蛋白的聚集和膜结合特性。令人惊讶的是，阻断丝氨酸磷酸化（S87A、S129A 和 S87A/S129A）或模拟它（S87D、S129D）改变了裂殖酵母中的α-突触核蛋白聚集。无论是阻断还是模拟这种磷酸化都会增加裂殖酵母中的内体膜结合，但仅模拟它会减少芽殖酵母中的质膜结合。丙氨酸-76 的极性取代突变（A76E 和 A76R）降低了芽殖酵母中α-突触核蛋白的膜结合，并降低了裂殖酵母中的聚集。这些酵母研究扩展了我们对丝氨酸磷酸化和丙氨酸-76 对α-突触核蛋白聚集的贡献的理解，并且是首次详细描述它们对α-突触核蛋白的质膜和内体膜结合的影响。
