The Vps35 D620N Mutation Linked to Parkinson's Disease Disrupts the Cargo Sorting Function of Retromer

Abstract

The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild-type Vps35. While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of α-synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD.

A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration

“…Mutations in VPS35, VPS26A and the retromer accessory protein DNAJC13 [43][44][45][46] have been associated with late-onset autosomal dominant Parkinson's disease (PD) [47][48][49][50]. Indeed, the PD-linked VPS35(p.D620N) mutation displays a reduced ability to associate with the actin polymerizing WASH (Wiskott-Aldrich syndrome protein and SCAR Homology) complex [51][52][53] which leads to altered endosome-to-Golgi transport and autophagosome formation [54,44,55,56]. Perturbed function of the WASH complex is also implicated in hereditary spastic paraplegia [57].…”

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

“…Several groups, including us, have noted that VPS35-retromer dysfunction has also been directly coupled to αSYN-related cytotoxicity. Retromer malfunction increases the lysosomal turnover of the mannose 6-phosphate receptor, thereby affecting the trafficking of cathepsin D (CTSD), a major lysosomal aspartyl protease that is involved in αSYN degradation (Follett et al 2014;Miura et al 2014). We found that the genetic ablation of Drosophila Vps35 not only induced the accumulation of the detergent-insoluble αSYN species in the central nervous system but also exacerbated both locomotor impairments and compound eye degeneration in human αSYN-transgenic flies .…”

Cellular functions of WASP family proteins at a glance

“…WASH is recruited to retromer-positive endosomal subdomains via the interaction of the extended C-terminal tail of FAM21 with the retromer subunit VPS35 (Harbour et al, 2012;Jia et al, 2012). Interestingly, a mutation in VPS35 (D620N) (Vilariño-Güell et al, 2011;Zimprich et al, 2011) that is associated with earlyonset Parkinson's disease has been shown to diminish the interaction of the SHRC with VPS35 and impair vesicular trafficking from the late endosome (Follett et al, 2013;McGough et al, 2014;Zavodszky et al, 2014). Studies in Drosophila have recently shown important roles for WASH in regulating integrin receptor trafficking and lysosome acidification (Nagel et al, 2017).…”