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.

中文翻译：

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与帕金森病相关的 Vps35 D620N 变体破坏了逆转录转运载体的形成

Retromer 核心复合物是一种内体支架，在协调内体系统内的蛋白质运输中起关键作用。在这里，我们使用 Vps35 D620N 拯救细胞模型描述了与帕金森病相关的 Vps35 D620N 在溶酶体系统中的作用。Vps35 D620N 完全挽救了逆转录酶敲除引起的溶酶体和自噬缺陷。类似于 Vps35 敲除细胞，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) 的内体到反式高尔基体网络运输在 Vps35 D620N 救援细胞中受损。表达 Vps35 D620N 变体的细胞内体形态发生了改变，导致结构更小、更圆、管状分支更少。在分子水平上，结合 Vps35 D620N 变体的逆转录酶与逆转录酶相关蛋白 wiskott-aldrich 综合征蛋白和 SCAR 同源物 (WASH) 和 SNX3 的结合降低，这些蛋白已知与逆转录酶结合以形成内体转运载体。因此，在存在 Vps35 D620N 的情况下，逆行蛋白质运输载体的部分缺陷代表了能够导致帕金森病的细胞状态改变。