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Review
. 2024 Apr 8;379(1899):20220384.
doi: 10.1098/rstb.2022.0384. Epub 2024 Feb 19.

VPS35 and retromer dysfunction in Parkinson's disease

Jordan Rowlands  1 , Darren J Moore  1
Affiliations
Review

VPS35 and retromer dysfunction in Parkinson's disease

Jordan Rowlands et al. Philos Trans R Soc Lond B Biol Sci. .

Abstract

The vacuolar protein sorting 35 ortholog (VPS35) 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 VPS35 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 VPS35-linked PD and sporadic PD suggest that defects observed in cellular and animal models with the D620N VPS35 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 VPS35-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'.

Keywords: Parkinson's disease (PD); VPS35; endosome; lysosome; retromer; vesicular sorting.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
Schematic diagram of the mammalian retromer complex and its associated proteins. Depicted are the retromer-interacting proteins from studies in mammalian cells. The retromer complex consisting of VPS26, VPS29 and VPS35 is essential for recycling of endosomal transmembrane protein cargo [13]. The retromer is depicted as a single trimer here, and proteins are grouped according to function, e.g. regulators of cargo-selective retromer complex and membrane association, SNX3, Rab7a and TBC1D5. Binding directly to VPS29, TBC1D5 is a member of Tre2-Bub2-Cdc16 (TBC) family of Rab GTPase-activating proteins (GAPs); it is believed to be associated with membrane recruitment of the retromer, has been shown to bind to autophagy marker LC3 and it has been implicated to have a role in mitophagy [–17]. The retromer facilitates two routes of cargo sorting: endosome-to-plasma membrane transport and endosome-to-trans-Golgi network (TGN) transport. Retromer-mediated sorting has been shown to be facilitated by association of the retromer with the pentameric WASH complex. Composed of SWIP/KIAA1033, WASH1, Strumpellin, CCDC53 and FAM21, the WASH complex is important for discrete sorting pathways by forming F-actin patches along endosomal tubes [10,18,19]. Arrows indicate relationships between respective proteins and colours indicate the cellular pathway involved, while dashed arrows indicate an interaction that has yet to be experimentally validated.
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