VPS54 encodes a critical subunit of the Golgi-associated retrograde protein (GARP) complex that mediates vesicle tethering and retrograde transport from endosomes to the trans-Golgi network (TGN) 1. The protein functions as a vesicle-tethering factor that is essential for proper intracellular protein sorting and maintaining cycling of mannose 6-phosphate receptors between the TGN and endosomes 2. VPS54 contains coiled-coil regions and multiple dileucine motifs, and is ubiquitously expressed across species 3. Loss of VPS54 function severely impairs retrograde transport of cholera toxin B subunit to the TGN and causes mis-sorting of mannose-6-phosphate receptors and their cargo proteins 2. The GARP complex is also required for efficient post-Golgi anterograde transport of cell-surface proteins 4. Disease relevance is established through the wobbler mouse model, where a destabilizing point mutation in Vps54 causes motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS) 1. Complete loss of VPS54 function results in embryonic lethality with extensive neural tube membrane blebbing 2. However, screening of human ALS patients revealed that VPS54 mutations are not a major cause of sporadic or familial ALS 5, suggesting species-specific differences in disease susceptibility.