VPS35

Among the genes related to familial PD, we are studying the vacuolar protein sorting 35 (VPS35) gene, also known as PARK17. The most common VPS35 mutation causes familial PD, and data both in mice and in cells show that VPS35 controls αSyn accumulation, meaning that a decrease in levels or activity of VPS35 is associated with an increase in αSyn aggregates and neuronal death. This evidence can be tied to key functions of VPS35 highlighted in recent studies, namely the ability to regulate the trafficking of proteins involved in αSyn degradation pathways. Although VPS35 controls mechanisms of direct relevance to PD, its value as a potential therapeutic target in PD is underestimated and understudied. We aim to validate the key role of VPS35 in promoting the clearance of αSyn in vitro and in vivo and its involvement in neuroprotection. Additionally, we are testing a specific VPS35-targeting small molecule that may itself be a promising drug candidate and could eventually step up to clinical trials in PD.

The endosome is in charge of cargo sorting and trafficking [1]. The retromer is composed of a stable heteropentameric complex comprised of VPS26, VPS29, and VPS35, of which VPS35 is the main stabilizing component plus a sorting nexin (SNX) protein dimer [4,13]. The VPS35 gene specifically encodes for the cargo-binding component of the retromer recognition core complex [9]. It operates the retrograde cargo transport from the endosome to the trans-Golgi network (TGN), a process that directly regulates intracellular cargo sorting and trafficking [4]. It can also return cargo from the endosome to the cell surface via the recycling pathway.

Mutation of the vacuolar protein sorting ortholog (VPS35) protein is a known cause of autosomal dominant Parkinson’s disease [9]. Mutations or deficiencies in parts of the retromer lead to endosomal and lysosomal dysfunction, inducing the miss-sorting of essential molecules and the accumulation of unwanted protein aggregates such as alpha-synuclein [1,12]. By disrupting the retrograde pathways, VPS35[D620N] mutation leads to defects in protein trafficking and lysosomal function[1]. In the cell, the retromer is responsible for transporting cation-independent mannose-6 phosphate receptor (CI-MPR) from the endosome to the TGN [12,13]. VPS35 also sorts cathepsins from the TGN to lysosomes [12]. (Define what cathepsins are) Although retromer assembly is not impaired in D620N mutant VPS35, trafficking and maturation of Cathepsin D, a CI-MPR ligand involved in the degradation of alpha-synuclein, is disrupted [5,13]. Other studies have demonstrated that CI-MPR sorting is retained in D620N mutant VPS35 and impaired sorting of Cathepsin D may account for the reduction in alpha-synuclein degradation in the lysosome [13].