Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA.
Philos Trans R Soc Lond B Biol Sci. 2024 Apr 8;379(1899):20220384. doi: 10.1098/rstb.2022.0384. Epub 2024 Feb 19.
The () gene encodes a core component of the retromer complex essential for the endosomal sorting and recycling of transmembrane cargo. Endo-lysosomal pathway deficits are suggested to play a role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Mutations in cause a late-onset, autosomal dominant form of PD, with a single missense mutation (D620N) shown to segregate with disease in PD families. Understanding how the PD-linked D620N mutation causes retromer dysfunction will provide valuable insight into the pathophysiology of PD and may advance the identification of therapeutics. D620N VPS35 can induce LRRK2 hyperactivation and impair endosomal recruitment of the WASH complex but is also linked to mitochondrial and autophagy-lysosomal pathway dysfunction and altered neurotransmitter receptor transport. The clinical similarities between -linked PD and sporadic PD suggest that defects observed in cellular and animal models with the mutation may provide valuable insights into sporadic disease. In this review, we highlight the current knowledge surrounding VPS35 and its role in retromer dysfunction in PD. We provide a critical discussion of the mechanisms implicated in -mediated neurodegeneration in PD, as well as the interplay between VPS35 and other PD-linked gene products. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.
()基因编码了内体分选和跨膜货物再循环所必需的逆转运体复合物的核心组成部分。内体溶酶体途径缺陷被认为在神经退行性疾病（包括帕金森病（PD））的发病机制中发挥作用。（）中的突变导致迟发性、常染色体显性形式的 PD，单个错义突变（D620N）在 PD 家族中与疾病分离。了解 PD 相关的 D620N 突变如何导致逆转运体功能障碍将为 PD 的病理生理学提供有价值的见解，并可能推进治疗剂的鉴定。D620N VPS35 可以诱导 LRRK2 过度激活并损害 WASH 复合物的内体募集，但也与线粒体和自噬溶酶体途径功能障碍以及神经递质受体运输改变有关。与 D620N 相关的 PD 与散发性 PD 之间的临床相似性表明，在携带突变的细胞和动物模型中观察到的缺陷可能为散发性疾病提供有价值的见解。在这篇综述中，我们强调了围绕 VPS35 及其在 PD 中逆转运体功能障碍中的作用的现有知识。我们对 PD 中与 VPS35 介导的神经退行性变相关的机制以及 VPS35 与其他 PD 相关基因产物之间的相互作用进行了批判性讨论。本文是关于“理解神经退行性疾病中的内体-溶酶体网络”的讨论会议的一部分。
