Department of Biosciences and Bioengineering , Indian Institute of Technology Bombay , Mumbai 400076 , India.
IITB-Monash Research Academy , Indian Institute of Technology Bombay , Mumbai 400076 , India.
ACS Chem Neurosci. 2018 Nov 21;9(11):2628-2638. doi: 10.1021/acschemneuro.8b00107. Epub 2018 Jul 3.
α-Synuclein (α-Syn) aggregation and amyloid formation are associated with loss of dopaminergic neurons in Parkinson's disease (PD). In addition, familial mutations in α-Syn are shown to be one of the definite causes of PD. Here we have extensively studied familial PD associated α-Syn G51D, H50Q, and E46K mutations using Drosophila model system. Our data showed that flies expressing α-Syn familial mutants have a shorter lifespan and exhibit more climbing defects compared to wild-type (WT) flies in an age-dependent manner. The immunofluorescence studies of the brain from the old flies showed more dopaminergic neuronal cell death in all mutants compared to WT. This adverse effect of α-Syn familial mutations is highly correlated with the sustained population of oligomer production and retention in mutant flies. Furthermore, this was supported by our in vitro studies, where significantly higher amount of oligomer was observed in mutants compared to WT. The data suggest that the sustained population of oligomer formation and retention could be a major cause of cell death in α-Syn familial mutants.
α-突触核蛋白（α-Syn）聚集和淀粉样形成与帕金森病（PD）中多巴胺能神经元的丧失有关。此外，α-Syn 的家族突变被证明是 PD 的明确原因之一。在这里，我们使用果蝇模型系统对与家族性 PD 相关的 α-Syn G51D、H50Q 和 E46K 突变进行了广泛研究。我们的数据表明，与野生型（WT）果蝇相比，表达 α-Syn 家族突变体的果蝇寿命更短，并且在年龄依赖性方面表现出更多的攀爬缺陷。来自老年果蝇大脑的免疫荧光研究表明，与 WT 相比，所有突变体中的多巴胺能神经元细胞死亡更多。α-Syn 家族突变的这种不良影响与突变体中寡聚物产生和保留的持续种群高度相关。此外，我们的体外研究也支持了这一观点，其中在突变体中观察到的寡聚物数量明显高于 WT。数据表明，寡聚物形成和保留的持续种群可能是 α-Syn 家族突变体中细胞死亡的主要原因。
