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Review
. 2022 Aug:170:105768.
doi: 10.1016/j.nbd.2022.105768. Epub 2022 May 16.

Understanding the contributions of VPS35 and the retromer in neurodegenerative disease

Erin T Williams  1 , Xi Chen  1 , P Anthony Otero  1 , Darren J Moore  2
Affiliations
Review

Understanding the contributions of VPS35 and the retromer in neurodegenerative disease

Erin T Williams et al. Neurobiol Dis. 2022 Aug.

Abstract

Perturbations of the endolysosomal pathway have been suggested to play an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Specifically, VPS35 and the retromer complex play an important role in the endolysosomal system and are implicated in the pathophysiology of these diseases. A single missense mutation in VPS35, Asp620Asn (D620N), is known to cause late-onset, autosomal dominant familial PD. In this review, we focus on the emerging role of the PD-linked D620N mutation in causing retromer dysfunction and dissect its implications in neurodegeneration. Additionally, we will discuss how VPS35 and the retromer are linked to AD, amyotrophic lateral sclerosis, and primary tauopathies. Interestingly, reduced levels of VPS35 and other retromer components have been observed in post-mortem brain tissue, suggesting a role for the retromer in the pathophysiology of these diseases. This review will provide a comprehensive dive into the mechanisms of VPS35 dysfunction in neurodegenerative diseases. Furthermore, we will highlight outstanding questions in the field and the retromer as a therapeutic target for neurodegenerative disease at large.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Autophagy; Cargo; Endosome; Golgi; LRRK2; Lysosome; Mitochondria; Parkinson's disease; Retromer complex; Tau; Tauopathies; VPS35; Vesicular sorting.

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Figures

Figure 1:
Figure 1:. Mammalian retromer complex and retrograde protein sorting.
The mammalian retromer complex, consisting of VPS26, VPS29, and VPS35, functions as a key recycling mechanism for endosomal transmembrane protein cargo [3]. The retromer is depicted here as a single trimer of VPS26, VPS29, and VPS35 (PDB ID: 6VAC), however recent data suggests that the retromer trimer can form dimers of trimers, tetramers of trimers, and oligomers of trimers [16]. The retromer localizes to the cytosolic face of the endosome where it is responsible for selecting and binding to transmembrane proteins. The retromer facilitates two routes of retrograde transport within the cell: endosome-to-trans-Golgi network (TGN) and endosome-to-plasma membrane transport. Retromer-mediated endosome-to-TGN transport was first demonstrated in yeast to be important for the delivery of acid hydrolases to the lysosome [1, 2]. Similarly, in mammalian cells, the retromer is responsible for transporting CI-MPR from the endosome to the TGN whereby acid hydrolases bind to CI-MPR and are delivered back to the endolysosomal system via retromer-independent mechanisms. Additionally, following retromer-independent endocytosis, the retromer has been shown to facilitate the recycling of plasma membrane receptors (i.e. β2-AR, GLUT1) from the endosome to the plasma membrane. In some cases, as with β2-AR and GLUT1, retromer-mediated trafficking can be facilitated through retromer association with the WASH complex. The WASH complex, composed of SWIP, Strumpellin, WASH1, FAM21, and CCDC53, facilitates discrete trafficking pathways by forming F-actin patches along the endosomal tubules [–21].
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