Investigating the GBA1-dependent regulation of GBA2 activity in Gaucher disease

Abstract

Glycosphingolipids (GSLs) are a large and heterogeneous class of lipids, whose function is equally versatile and complex. They consist of a membrane anchor, ceramide, and different kinds of sugar head groups. Glucosylceramide (GlcCer) is the simplest GSL and serves as a building block for the synthesis of more complex GSLs. GlcCer is degraded either in the lysosome by the acid beta-glucosidase GBA1 or by the non-lysosomal beta-glucosidase GBA2, which is associated with membranes at the Golgi and ER. It is not known whether their distinct localisation points towards a different cellular function. Accumulation of GlcCer due to the lack of GBA2 results in male infertility, whereas various mutations in the GBA1 gene and loss of GBA1 activity cause the lipid-storage disorder Gaucher disease with different clinical subtypes. However, no genotype-phenotype correlation has been identified so far. The role of GBA2 in Gaucher disease pathology and its relationship to GBA1 is not well understood. My results reveal a GBA1-dependent down-regulation of GBA2 activity in patients suffering from Gaucher disease. I show that sphingosine, the cytotoxic metabolite accumulating in Gaucher cells through the action of GBA2, directly binds to GBA2 and inhibits its activity. I propose a negative feed-back loop that inhibits GBA2 activity in Gaucher cells through the action of sphingosine, preventing its further accumulation and cytotoxicity. My findings add a new chapter to the understanding of the complex molecular mechanism underlying Gaucher disease and the regulation of beta-glucosidase activity in general.