Glucosylceramidase beta (GBA1)

Glucosylceramidase beta, commonly known as glucocerebrosidase (GCase), is a lysosomal hydrolase encoded by the GBA1 gene that plays a critical role in sphingolipid metabolism by cleaving glucosylceramide into glucose and ceramide. Inherited biallelic mutations in GBA1 result in Gaucher disease, a lysosomal storage disorder characterized by the accumulation of undegraded substrates in macrophages, leading to hepatosplenomegaly, bone disease, and cytopenia. Beyond its role in Gaucher disease, GBA1 mutations are recognized as the most significant genetic risk factor for Parkinson's disease and Lewy body dementia, where reduced enzyme activity is thought to impair the autophagy-lysosomal pathway and promote the aggregation of alpha-synuclein. Therapeutic interventions include enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) for systemic Gaucher disease, while current research focuses on small-molecule chaperones, enzyme activators, and gene therapies to restore GCase function in the central nervous system to treat neurodegenerative synucleinopathies.

Other names

GlucocerebrosidaseAcid beta-glucosidaseGCaseGBAGCBGLUCLysosomal acid glucosylceramidaseD-glucosyl-N-acylsphingosine glucohydrolase

Enzyme replacement therapy (ERT) to restore catalytic activity, substrate reduction therapy (SRT) to decrease lipid accumulation, pharmacological chaperone therapy (PCT) to stabilize enzyme folding and trafficking, and gene therapy to increase GBA1 expression and restore enzyme levels.