Vacuolar protein sorting-associated protein 26A

VPS26A is a core component of the retromer cargo-selective complex, a protein trafficking hub that prevents missorting of transmembrane cargo into lysosomal degradation pathways (UniProt: O75436). It mediates retrograde transport from endosomes to the trans-Golgi network and endosome-to-plasma membrane recycling across multiple retromer variants (SNX-BAR, SNX3, and SNX27), and interacts with regulatory proteins including the WASH complex and TBC1D5. VPS26A also regulates trafficking of APP-processing machinery components such as SORL1.

VPS26A is implicated in Alzheimer's disease pathology through its role in sorting and processing of APP. In post-mortem AD brain tissue analyzed via quantitative proteomics across four subcellular fractions (P2, P3, S2, S3), VPS26A showed ambiguous direction of change with a mean log2 fold-change of −0.09 relative to age-matched controls (Chaparral AD proteomics), indicating minimal overall abundance difference but potentially informative subcellular redistribution. This modest change underscores the complex relationship between retromer function and amyloid precursor protein metabolism in neurodegeneration.