Vacuolar protein sorting-associated protein 53 homolog

VPS53 (vacuolar protein sorting-associated protein 53 homolog) is a component of the GARP and EARP protein complexes involved in membrane trafficking (UniProt: Q5VIR6). The GARP complex mediates retrograde transport from early and late endosomes to the trans-Golgi network, maintaining cycling of mannose 6-phosphate receptors necessary for lysosomal enzyme sorting. The EARP complex promotes recycling of transferrin receptor to the plasma membrane via Rab4-positive endosomes. These functions are critical for intracellular protein trafficking and lysosomal homeostasis.

VPS53 is associated with pontocerebellar hypoplasia 2E (PCH2E), a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, intellectual disability, and early-onset epilepsy (UniProt: Q5VIR6). The protein's roles in endosomal-lysosomal trafficking implicate it in neuronal cell maintenance.

In Alzheimer's disease, VPS53 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.51 across subcellular fractions (Chaparral AD proteomics). This reduction may impair endosomal recycling and lysosomal function, processes increasingly recognized as disrupted in AD pathogenesis.