Vacuolar protein sorting-associated protein 33A

VPS33A (Vacuolar protein sorting-associated protein 33A) is a 596-amino-acid protein that functions as a core component of endosomal tethering complexes involved in vesicle-mediated protein trafficking. It plays a critical role in the Rab5-to-Rab7 endosome conversion and mediates fusion of endosomes and autophagosomes with lysosomes through interactions with SNAREs and other tethering machinery (UniProt: Q96AX1). The protein operates within lysosomal trafficking pathways and endocytic membrane transport systems essential for cellular cargo degradation.

Loss-of-function mutations in VPS33A cause mucopolysaccharidosis-plus syndrome (MPSPS), an autosomal recessive lysosomal storage disease characterized by severe glycosaminoglycan accumulation, hepatosplenomegaly, developmental delay, and early lethality (UniProt: Q96AX1). The protein's essential role in autophagosome-lysosome fusion highlights its importance in cellular waste management.

VPS33A is significantly downregulated in Alzheimer's disease brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.83 across post-mortem samples analyzed by quantitative mass spectrometry. This reduction may impair autophagic clearance pathways implicated in amyloid and tau pathology, linking lysosomal dysfunction to AD pathogenesis.