Parkinson's Disease Associated α-Synuclein Familial Mutants Promote Dopaminergic Neuronal Death in Drosophila melanogaster.,ACS Chemical Neuroscience

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Parkinson's Disease Associated α-Synuclein Familial Mutants Promote Dopaminergic Neuronal Death in Drosophila melanogaster.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-07-03 , DOI: 10.1021/acschemneuro.8b00107
Ganesh M Mohite ₁ , Saumya Dwivedi ₁ , Subhadeep Das _{1,

2} , Rakesh Kumar ₁ , Sravya Paluri ₁ , Surabhi Mehra ₁ , Neha Ruhela ₁ , Arunima S ₁ , Narendra Nath Jha ₁ , Samir K Maji ₁

Affiliation

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.

中文翻译：

帕金森氏病相关的α-突触核蛋白家族突变体促进果蝇的多巴胺能神经元死亡。

α-突触核蛋白（α-Syn）聚集和淀粉样蛋白的形成与帕金森氏病（PD）中多巴胺能神经元的丢失有关。另外，α-Syn中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广泛研究了与家族性PD相关的α-SynG51D，H50Q和E46K突变。我们的数据显示，与野生型（WT）蝇相比，表达α-Syn家族突变体的蝇具有较短的寿命，并表现出更多的攀爬缺陷，并且其依赖年龄。与野生型相比，老蝇对大脑的免疫荧光研究显示，所有突变体中多巴胺能神经元细胞死亡的发生率更高。α-Syn家族突变的不利影响与寡聚体的持续产生和突变果蝇的滞留高度相关。此外，我们的体外研究支持了这一点，在突变体中观察到的寡聚体量明显高于野生型。数据表明，低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。

更新日期：2018-06-15

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