Calcineurin/NFAT信号通路在alpha-synuclein所致多巴胺能神经元损伤中的作用及其相应的药物干预

帕金森病（Parkinson's disease, PD）是一种以黑质纹状体通路的病变为主要特征的神经退行性疾病。PD两个主要的病理学特征，一是中脑黑质致密部（SNC）多巴胺能神经元的丧失；二是SNC区域发现的称为路易体（ LBs）的包涵体。研究发现，α-synuclein蛋白是组成LBs的主要成分。遗传学研究结果显示编码α-synuclein的SNCA基因突变导致的氨基酸突变，如A53T或该基因染色体座位三倍扩增等都与家族性PD的发病有着直接关系。我们课题组实验研究和文献调研发现，钙调神经磷酸酶（Calcineurin,CN）/NFAT信号通路在PD神经元存活中发挥重要作用。本课题将利用过表达野生型以及突变型A53Tα-synuclein的细胞以及A53T小鼠研究CN/NFAT信号通路在PD多巴胺能神经元丢失中的作用机制，并利用我们实验室前期已经筛选得到的药物进行干预，寻找新的药物靶点。

Parkinson's disease (PD) is pathologically characterized by a preferential loss of midbrain dopaminergic neurons and the presence of α-synuclein-positive intracytoplasmic inclusions named Lewy bodies (LBs). Whereas both missense and multiplication mutaions of α-synuclein cause the early-onset autosomal dominant familial forms of PD, the α-synuclein gene locus also associates with the common sporadic PD. Together, these data point out a prominent role of α-synuclein in the pathogenesis of PD. However, the molecular pathogenic processes by which α-synuclein causes the degeneration of midbrain dopaminergic neurons remains elusive. Our recent results show that calcineurin/NFAT signaling pathway plays an important role on dopaminergic dysfunction. The present study is to systematically investigate the CN/NFAT pathway in α-synuclein-dependent neuron loss using transfected cells and A53T double transgenic mice. This new target may be useful for screening and testing new PD therapeutic drugs.