Glucosylceramidase beta (GBA1) (GBA1)

Glucosylceramidase beta (GBA1), also known as acid beta-glucosidase, is a lysosomal enzyme responsible for the hydrolysis of glucosylceramide into glucose and ceramide (UniProt P04062). Mutations in the GBA1 gene lead to a deficiency in this enzyme's activity, resulting in the accumulation of glucosylceramide and glucosylsphingosine within lysosomes, which is the hallmark of Gaucher disease (NIH: Genetics Home Reference). Furthermore, GBA1 mutations are the most significant genetic risk factor for Parkinson's disease and Dementia with Lewy bodies, where enzyme deficiency is linked to the toxic accumulation of alpha-synuclein (Sidransky et al., 2009, NEJM). In the central nervous system, the loss of GBA1 function impairs lysosomal proteostasis and promotes neurodegeneration (PubMed: 21725313). Therapeutic strategies for CNS involvement include gene therapy (e.g., PR001/LY3884961) designed to deliver a functional hGBA1 gene to neurons, thereby restoring enzymatic activity and promoting the clearance of protein aggregates (Prevail Therapeutics). This approach is particularly relevant because standard enzyme replacement therapies cannot cross the blood-brain barrier effectively (PubMed: 30243540). By targeting CNS neurons directly, gene delivery aims to provide a long-term source of the enzyme within the affected tissue to mitigate disease progression.

Other names

Acid beta-glucosidaseGlucocerebrosidaseGBAGCaseGlucosylceramidase beta 1GCB

Restoration of lysosomal glucosylceramidase activity through gene augmentation, enzyme replacement, or pharmacological chaperoning to reduce toxic substrate accumulation.