Non-lysosomal glucosylceramidase (GBA2) (GBA2)

Non-lysosomal glucosylceramidase (GBA2) is a membrane-associated enzyme located primarily at the endoplasmic reticulum and Golgi apparatus, where it catalyzes the hydrolysis of glucosylceramide into glucose and ceramide (UniProt Q9HCG7). Unlike the lysosomal GBA1, GBA2 operates at a neutral pH and plays a distinct role in maintaining sphingolipid homeostasis and signaling within the cell (PubMed: 22822173). Mutations in the GBA2 gene are associated with autosomal recessive neurodegenerative disorders, specifically hereditary spastic paraplegia type 46 and cerebellar ataxia (NCBI Gene: 57704). In the context of lysosomal storage diseases such as Gaucher and Niemann-Pick type C, GBA2 activity is often increased, contributing to the pathophysiology; thus, its inhibition is considered a potential therapeutic approach (PubMed: 23064267). Pharmacological agents like the iminosugar miglustat are known to potently inhibit GBA2, though this interaction is also linked to side effects such as reversible male infertility in animal models (PubMed: 12032315).

Other names

Non-lysosomal beta-glucosidase 2Glucosylceramidase 2Bile acid beta-glucosidaseBeta-glucosidase 2

Inhibition of non-lysosomal glucosylceramide hydrolysis to modulate cellular sphingolipid levels and mitigate neurodegeneration or lysosomal storage pathology.