School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
Institute for Molecular Biosciences and Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland, Australia.
Traffic. 2021 Apr;22(4):123-136. doi: 10.1111/tra.12779. Epub 2021 Jan 22.
Retromer core complex is an endosomal scaffold that plays a critical role in orchestrating protein trafficking within the endosomal system. Here we characterized the effect of the Parkinson's disease-linked Vps35 D620N in the endo-lysosomal system using Vps35 D620N rescue cell models. Vps35 D620N fully rescues the lysosomal and autophagy defects caused by retromer knock-out. Analogous to Vps35 knock out cells, the endosome-to-trans-Golgi network transport of cation-independent mannose 6-phosphate receptor (CI-M6PR) is impaired in Vps35 D620N rescue cells because of a reduced capacity to form endosome transport carriers. Cells expressing the Vps35 D620N variant have altered endosomal morphology, resulting in smaller, rounder structures with less tubule-like branches. At the molecular level retromer incorporating Vps35 D620N variant has a decreased binding to retromer associated proteins wiskott-aldrich syndrome protein and SCAR homologue (WASH) and SNX3 which are known to associate with retromer to form the endosome transport carriers. Hence, the partial defects on retrograde protein trafficking carriers in the presence of Vps35 D620N represents an altered cellular state able to cause Parkinson's disease.
Retromer 核心复合物是一种内体支架，在协调内体系统中的蛋白质运输中起着关键作用。在这里，我们使用帕金森病相关的 Vps35 D620N 挽救细胞模型来描述 Vps35 D620N 在内体-溶酶体系统中的作用。Vps35 D620N 完全挽救了 retromer 敲除引起的溶酶体和自噬缺陷。与 Vps35 敲除细胞类似，由于形成内体运输载体的能力降低，阳离子非依赖性甘露糖 6-磷酸受体 (CI-M6PR) 的内体-反式高尔基体网络运输在 Vps35 D620N 挽救细胞中受损。表达 Vps35 D620N 变体的细胞具有改变的内体形态，导致更小、更圆的结构，管状分支较少。在分子水平上，与 retromer 相关的蛋白 wiskott-aldrich 综合征蛋白和 SCAR 同源物 (WASH) 和 SNX3 的结合减少，已知它们与 retromer 结合形成内体运输载体。因此，在存在 Vps35 D620N 的情况下，逆行蛋白运输载体的部分缺陷代表了一种改变的细胞状态，能够导致帕金森病。
