GBA2 is a non-lysosomal glucosylceramidase that catalyzes hydrolysis of glucosylceramides to glucose and ceramides 1. Beyond this primary function, GBA2 exhibits glucosyltransferase activity, transferring glucose from glucosylceramide to cholesterol and participating in bile acid metabolism 2. The enzyme localizes to the endoplasmic reticulum and Golgi apparatus, where it regulates glycosphingolipid catabolism affecting cellular signaling and membrane dynamics 3. Loss of GBA2 function causes glucosylceramide accumulation and impairs neuronal development. Biallelic GBA2 mutations cause spastic paraplegia type 46 (SPG46), an autosomal recessive hereditary spastic paraplegia presenting with progressive spasticity, ataxia, and neurological decline 4. Patients exhibit variable phenotypes including cerebellar ataxia and Marinesco-Sjögren-like features 5. SPG46-associated mutations predominantly reduce GBA2 catalytic activity and disrupt protein-protein interactions 6. GBA2 loss selectively affects F-actin dynamics and neurite outgrowth in cerebellar neurons, mechanistically linking glycosphingolipid breakdown to neurological dysfunction 6. Beyond neurological disease, GBA2 suppresses melanoma progression by promoting ceramide-mediated endoplasmic reticulum stress and apoptosis, with reduced GBA2 expression in melanoma tissue 7.