Glucocerebrosidase (GBA) (GBA)

Glucocerebrosidase (GBA) is a critical lysosomal enzyme responsible for the hydrolysis of glucosylceramide into glucose and ceramide (UniProt: P04062). A deficiency in this enzyme's activity, typically due to biallelic mutations in the GBA1 gene, leads to the lysosomal accumulation of glucosylceramide and glucosylsphingosine, primarily within macrophages (StatPearls: Gaucher Disease). This pathological state results in Gaucher disease, which manifests as hepatosplenomegaly, cytopenias, and skeletal abnormalities. Beyond Gaucher disease, GBA dysfunction is recognized as a major genetic risk factor for Parkinson's disease, where it is thought to promote the aggregation of alpha-synuclein (PubMed: PMC4981740). Current therapeutic interventions include enzyme replacement therapy (ERT) to restore enzymatic activity and substrate reduction therapy (SRT) to limit the accumulation of the enzyme's substrate (DrugBank: DB00053). Emerging research also focuses on pharmacological chaperones and gene therapies to address the underlying protein misfolding and genetic deficiency.

Other names

Acid beta-glucosidaseGBA1GlucosylceramidaseD-glucosyl-N-acylsphingosine glucohydrolaseLysosomal acid glucosylceramidase

Enzyme replacement therapy (ERT) provides exogenous functional enzyme to replace the deficient endogenous protein; substrate reduction therapy (SRT) inhibits glucosylceramide synthase to decrease the production of the substrate; pharmacological chaperones stabilize misfolded enzyme variants to enhance their trafficking to the lysosome.