VPS35, the Retromer Complex and Parkinson's Disease

Abstract

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies. In this review, we focus on the current knowledge surrounding VPS35 and its role in PD. We provide a critical discussion of the emerging data regarding the mechanisms underlying mutant VPS35-mediated neurodegeneration gleaned from genetic cell and animal models and highlight recent advances that may provide insight into the interplay between VPS35 and several other PD-linked gene products (i.e. α-synuclein, LRRK2 and parkin) in PD. Present data support a role for perturbed VPS35 and retromer function in the pathogenesis of PD.

Keywords: LRRK2; Parkinson’s disease (PD); VPS35; autophagy; endosomal sorting; lysosome; mitochondria; parkin; retromer; α-synuclein.

Fig.1

Retromer-regulated retrograde transport of endosomal-associated protein cargo. The retromer, along with retromer-associated proteins that assist in membrane binding (Snx3 and Rab7a), is responsible for the retrograde transport of several cargo proteins from the endosomal network to either the trans-Golgi network (TGN) or the plasma membrane. VPS35, along with VPS26 and VPS29, sit at the endosomal membrane and recognize cargo (transmembrane proteins) to be sorted. Two canonical cargo proteins that the retromer is responsible for transporting are the mannose-6-phosphate receptor (CI-MPR) and the β2-adrenergic receptor (β2-AR). These two examples demonstrate the two major routes of transport that are facilitated by the retromer [34]. CI-MPR is responsible for delivering acid hydrolases (cathepsin D, for example) to the endosome for eventual delivery to the lysosome. While other mechanisms are responsible for delivering CI-MPR with its ligand to the endosome, the retromer facilitates the retrieval of CI-MPR to the TGN to bind more ligand, which will eventually make its way to the endosome once again [85]. On the other hand, β2-AR is recycled from the endosome to the plasma membrane where it will stay until activated. Although the retromer is not responsible for the initial endocytosis of β2-AR at the plasma membrane, its role in recycling the receptor back to the plasma membrane prevents it from lysosomal degradation [48].