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

探索 Rab GTPases 在帕金森病中的治疗潜力

基本信息

批准号：
1853069
负责人：
金额：
--
依托单位：
University of Leicester
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1853069
关键词：
Exploring therapeutic potential Rab GTPases

项目摘要

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.

帕金森病（PD）是第二常见的神经退行性疾病，其特征在于多巴胺能神经元的损失和错误折叠的突触核蛋白（aSyn）的积累。异常的aSyn聚集和随后的扰动囊泡运输可能有助于神经变性。Rab GTP酶在细胞内的囊泡运输中起关键作用，并与PD的发病机制有关。我们已经发现Rab11和Rab8a都可以强烈抑制PD模型中的疾病表型。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靶向Rab GT3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，其中一个子集将在本项目中进行研究。学生将使用生物化学和显微镜方法评估候选Rabs对aSyn依赖性疾病相关表型的调节。将使用神经元中突触囊泡的荧光和超微结构成像来检查由于aSyn引起的突触囊泡释放和Rab定位的改变。还将检查Rabs对果蝇中aSyn疾病表型的影响。这项工作将提供重要的洞察机制和治疗潜力的Rab GTP酶在PD。