The Role of VPS35 in the Pathobiology of Parkinson's Disease

Abstract

The vacuolar protein sorting 35 (VPS35) gene located on chromosome 16 has recently emerged as a cause of late-onset familial Parkinson's disease (PD) (PARK17). The gene encodes a 796-residue protein nearly ubiquitously expressed in human tissues. The protein localizes on endosomes where it assembles with other peripheral membrane proteins to form the retromer complex. How VPS35 mutations induce dopaminergic neuron degeneration in humans is still unclear. Because the retromer complex recycles the receptors that mediate the transport of hydrolase to lysosome, it has been suggested that VPS35 mutations lead to impaired lysosomal and autophagy function. Recent studies also demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis, suggesting that VPS35 mutations elicit mitochondrial dysfunction. More recent studies have identified a key role of VPS35 in neurotransmission, whilst others reported a functional interaction between VPS35 and other genes associated with familial PD, including α-SYNUCLEIN-PARKIN-LRRK2. Here, we review the biological role of VPS35 protein, the VPS35 mutations identified in human PD patients, and the potential molecular mechanism by which VPS35 mutations can induce progressive neurodegeneration in PD.

Keywords: PARK17; Parkinson’s disease; Retromer complex; VPS35.

Fig. 1

Orthologous sequence alignment of the VPS35 protein. Orthologous sequences were obtained from Ensembl, and aligned using ClustalOmega. XENTR is sequence from Xenopus tropicalis, CHICK from Gallus gallus, RAT from Rattus norvegicus, MOUSE from Mus musculus, GORGO from Gorilla gorilla, CANLF from Canis lupus familiaris, PIG from Sus scrofa, HUMAN from Homo sapiens, PANTR from Pan troglodytes

Fig. 2

Diagram showing the role of VPS35 in retrieval of the mannose-6-phosphate receptor (CI-MPR) to the trans-Golgi network. VPS35, along with VPS26 and VPS29, are located on the endosomal membrane and recognize the cargo (transmembrane proteins) to be sorted. Retromer-associated proteins assist in membrane binding