VMAT2逆膜运输的异常调节及其在帕金森病发病机制中的作用

As a devastating neurodegenerative disease affecting aging population, Parkinson disease (PD) remains pathogenetically unclear. Recently numerous studies have unveiled several sporadic PD related genes with pathogenic mutations. There are also evidence for their potential subcellular interference in endosome-to-TGN retrograde membrane trafficking of membrane proteins. However, little is known for their membrane protein target(s) on which altered membrane trafficking may convey the selective and progressive pathological processes associated with PD clinic. Vesicular monoamine transporter 2 (VMAT2), a monoamine neuron specific expressed membrane protein, was originally identified for its role in protecting dopaminergic neurons from neurotoxin MPP+ and later for its association with PD pathogenesis. Recently we have experimentally demonstrated that VMAT2 can specifically interact with sorting nexin 5, a major component of retromer complex involved in the retrograde trafficking. Thus we hypothesize that PD mutants interference with the retrograde trafficking of VMAT2 and hence its vesicular targeting. And then the reduced neuroprotective capacity of VMAT2 will lead to a series of cellular pathogenesis including oxidative stress and protein aggregation. We will use molecular and cellular approaches to unveil the molecular mechanisms underlying vesicular targeting of VMAT2 and how PD mutants alter this process that may lead to neurodegeneration. We believe that this study may help us find a novel therapeutic concept in reduce or reverse the clinical PD processes.

作为危害老年人群的顽症，帕金森病(PD)的发病机制仍不清楚。近年来大量研究发现PD相关基因如LRRK2和Vps35的突变都与亚细胞保守的“逆膜运输”的调节失常相关，然而无法解释这些基本生物过程的失常如何选择性导致了PD中脑黒质多巴胺能神经元受损。囊泡单胺转运蛋白2（VMAT2) 具有阻抗导致PD模型的神经毒的重要保护功能且特异性的在单胺能神经元表达并与PD病理密切相关；我们近期大量实验结果表明其表达、囊泡膜定位及功能都通过与逆膜复合体中的分选蛋白5 (SNX5)结合而受逆膜运输的调节。故我们假设PD突变蛋白经干扰VMAT2的逆膜运输来削弱其神经保护作用，进而引起PD多因素的退行性病变。本课题将用分子细胞学手段在体内外系统中探讨 VMAT2的逆膜运输及囊泡膜定位的分子机制，以及PD基因突变如何削弱其对神经元的保护作用而导致病理过程，为找到终止和逆转帕金森病的病理过程的分子药物打下坚实基础。

作为常见的老年神经退行性病，帕金森病(PD)的发病机制仍不清楚。近年来大量研究发现PD相关基因如LRRK2和Vps35的突变都与亚细胞保守的“逆膜运输”的调节失常相关，然而无法解释这些基本生物过程的失常如何选择性导致了PD中脑黒质多巴胺能神经元受损。囊泡单胺转运蛋白2（VMAT2) 具有阻抗导致PD模型的神经毒的重要保护功能，且特异性的在单胺能神经元表达并与PD病理密切相关；本基金支持我们近几年在多方面探讨了VMAT2的表达、囊泡膜定位及功能如何通过与逆膜复合体中的分选蛋白5 (SNX5)结合而受逆膜运输的调节，同时阐明了PD突变蛋白，包括逆膜运输复合体中的VPS35，LRRK2和Rab29等经干扰VMAT2的逆膜运输来削弱其神经保护作用，进而引起PD多因素的退行性病变。本课题进一步支持了数个新的创新性课题的启动和发展，如逆膜运输复合体的功能调节中TBC1D5的参与及功能，LRRK2的结合蛋白MRG，Rab29及Prx2如何调节前者的GTP酶活性及磷酸化酶的活性而参与抑制LRRK2的致病过程，在生化，细胞和在体动物水平全方位的揭示VMAT2的功能调节及其与PD发病中的相关细胞机制，为找到终止和逆转帕金森病的病理过程的分子药物打下坚实的理论基础。