Beijing Institute for Neuroscience, Capital Medical University, Beijing Center of Neural Regeneration and Repair, China.
Acta Histochem. 2011 Jan;113(1):32-5. doi: 10.1016/j.acthis.2009.07.007. Epub 2009 Aug 14.
Hyperphosphorylated α-synuclein is considered an important event in the pathogenesis of Parkinson's disease but its function remains elusive. In this study we provide evidence that tyrosine hydroxylase (TH) expression was unaffected by overexpression of wild-type and phospho-mimic mutant α-synuclein (S129D) in dopaminergic MN9D cells. However, α-synuclein overexpression evidently inhibited TH phosphorylation at Ser40 and dopamine synthesis, while α-synuclein (S129D) mutant enhanced TH phosphorylation and dopamine synthesis. This phospho-mimic mutant prevented wild-type α-synuclein cytotoxicity to MN9D cells, which might be due to aggregation of mutant α-synuclein in the cytoplasm and nuclei. These results demonstrated that phosphorylation at Ser129 was involved in the regulation of TH activity, as well as in eliminating the neurotoxicity of wild-type α-synuclein overexpression in MN9D cells.
过度磷酸化的α-突触核蛋白被认为是帕金森病发病机制中的一个重要事件，但它的功能仍不清楚。在这项研究中，我们提供的证据表明，酪氨酸羟化酶（TH）的表达不受野生型和磷酸模拟突变α-突触核蛋白（S129D）在多巴胺能 MN9D 细胞中的过表达的影响。然而，α-突触核蛋白过表达明显抑制了 Ser40 的 TH 磷酸化和多巴胺的合成，而α-突触核蛋白（S129D）突变增强了 TH 磷酸化和多巴胺的合成。这种磷酸模拟突变阻止了野生型α-突触核蛋白对 MN9D 细胞的毒性，这可能是由于突变型α-突触核蛋白在细胞质和细胞核中的聚集。这些结果表明，Ser129 的磷酸化参与了 TH 活性的调节，以及消除 MN9D 细胞中野生型α-突触核蛋白过表达的神经毒性。
