Vacuolar protein sorting-associated protein 35

VPS35 (vacuolar protein sorting-associated protein 35) is a core component of the retromer cargo-selective complex, which functions to prevent missorting of transmembrane proteins into the lysosomal degradation pathway (UniProt: Q96QK1). The protein mediates retrograde transport from endosomes to the trans-Golgi network and endosome-to-plasma membrane recycling of diverse cargo proteins, including lysosomal enzyme receptors and immunoglobulin receptors. VPS35 associates with additional complexes such as WASH and acts as a recruitment hub for retromer complex variants.

VPS35 is implicated in Parkinson disease 17 (PARK17), an autosomal dominant neurodegenerative disorder characterized by loss of dopaminergic neurons and Lewy body pathology (UniProt: Q96QK1). The protein's role in endosomal trafficking and protein sorting is relevant to neuronal homeostasis and protein quality control.

In Alzheimer's disease, VPS35 shows ambiguous regulation across subcellular fractions from post-mortem AD brain (Chaparral AD proteomics). The mean log2 fold-change is −0.22, suggesting modest overall downregulation or variable compartment-specific changes relative to age-matched controls. This pattern is consistent with potential disruption of endosomal-sorting pathways in AD neurodegeneration.