Exploring the therapeutic potential of Rab GTPases in Parkinson's disease

帕金森病（PD）是第二大最常见的神经退行性疾病，其特征是多巴胺能神经元的丧失和错误折叠的突触核蛋白（aSyn）的积累。异常的aSyn聚集和随之而来的囊泡运输紊乱可能导致神经退行性变。Rab gtpase在细胞的囊泡运输中起关键作用，并与PD的发病机制有关。我们发现Rab11和Rab8a都能强烈抑制PD模型的疾病表型。然而，尚未在PD模型中对60个Rab家族成员进行系统测试，并且缺乏针对这些蛋白质的治疗策略。我们最近在哺乳动物细胞中进行了针对Rab GTPase基因的siRNA筛选，以鉴定调节aSyn聚集的基因。我们确定了22个基因，其中的一个子集将在本项目中进行研究。学生将使用生化和显微镜方法评估候选Rabs对非依赖性疾病相关表型的调节。我们将利用神经元突触囊泡的荧光和超微结构成像来检测aSyn对突触囊泡释放和Rab定位的影响。Rabs对果蝇aSyn疾病表型的影响也将被研究。这项工作将为Rab GTPases在PD中的作用机制和治疗潜力提供重要的见解。

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons and the accumulation of misfolded synuclein (aSyn). Aberrant aSyn aggregation and consequent perturbed vesicular trafficking likely contribute to neurodegeneration. Rab GTPases play critical roles in vesicular trafficking in the cell, and have been implicated in the pathogenesis of PD. We have found that both Rab11 and Rab8a can strongly suppress disease phenotypes in models of PD. However, systematic testing of the 60 Rab family members in PD models has not been performed, and therapeutic strategies targeting these proteins are lacking. We recently performed a siRNA screen targeting Rab GTPase genes in mammalian cells to identify genes which modulate aSyn aggregation. We identified 22 genes, a subset of which will be investigated in this project. The student will assess modulation of aSyn-dependent disease-related phenotypes by candidate Rabs using biochemical and microscopy approaches. Alterations in synaptic vesicular release and Rab localisation due to aSyn will be examined using fluorescence and ultrastructural imaging of synaptic vesicles in neurons. The effects of Rabs upon aSyn disease phenotypes in Drosophila will also be examined. This work will provide important insight into the mechanisms and therapeutic potential of Rab GTPases in PD.