Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Hum Mol Genet. 2010 Jun 1;19(11):2087-98. doi: 10.1093/hmg/ddq086. Epub 2010 Feb 25.
Genetic alterations in alpha-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an alpha-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in alpha-synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T alpha-synuclein double-transgenic mice survived longer than A53T alpha-synuclein single-transgenic mice. There were attenuated A53T alpha-synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of alpha-synucleinopathy and play a neuroprotective role against A53T alpha-synuclein toxicity in vivo.
α-突触核蛋白的遗传改变导致常染色体显性家族性帕金森病，并可能导致散发性帕金森病（PD）。突触核蛋白-1 是一种与α-突触核蛋白相互作用的蛋白质，与与蛋白聚集相关的 PD 发病机制有关。目前，突触核蛋白-1 在与α-突触核蛋白相关的发病机制中的体内作用尚未完全了解。我们使用鼠朊蛋白启动子，生成了突触核蛋白-1 转基因小鼠，但这些小鼠没有表现出 PD 样表型。然而，突触核蛋白-1/A53T α-突触核蛋白双转基因小鼠的存活时间长于 A53T α-突触核蛋白单转基因小鼠。双转基因小鼠中，A53T α-突触核蛋白诱导的运动异常减弱，星形胶质细胞反应和神经元变性减少。突触核蛋白-1 的过表达降低了 caspase-3 的激活，增加了 beclin-1 和 LC3 II 的表达，并促进了聚集物样结构的形成，这表明突触核蛋白-1 改变了多种细胞途径以防止神经元变性。这些研究表明，突触核蛋白-1 可以减轻α-突触核蛋白病的严重程度，并在体内发挥对 A53T α-突触核蛋白毒性的神经保护作用。
