Retromer is a heteropentameric complex consisting of a sorting nexin (SNX) dimer and a VPS26-VPS29-VPS35 trimer. The complex associates with the cytosolic face of endosomes and mediates transport of transmembrane protein cargo via tubular endosome extension. Evidence suggests retromer sequesters membrane-bound cargo proteins from vacuolar endosomes into retrograde transport intermediates, thus preventing their default delivery to lysosomes for degradation. The best characterized cargos are the acid hydrolase receptors: for example; vps10 in yeast and mannose 6-phosphate receptor in mammals. However recent studies demonstrate retromer dependency in a variety of other trafficking events including endosome to surface membrane delivery of neurotransmitter receptors.
We recently uncovered an aspartic-acid-to-asparagine mutation within VPS35 (pD620N; DN) as a genetic determinant of autosomal-dominant, late-onset parkinsonism.
We hypothesize that loss (or gain) of VPS35-dependent trafficking of neuronal substrates neurotransmitter receptor will lead to protracted neuronal dysfunction and eventual pathophysiology reminiscent of Parkinson’s Disease.
Aims & Expected Results
We are currently identifying which neurotransmitter receptor subunits are trafficked by VPS35 and how the D620N mutation may affect the trafficking, localization and activity of these subunits. Once we have defined a dysfunction, pharmacology will be used to reverse any defect imposed by the mutation and the functional consequence of this reversal will be assessed in animal models harbouring the mutation.