Gaucher disease (GD) is a lysosomal storage disorder resulting from an inborn reduced activity or deficiency of glucocerebrosidase due mainly to mutations in the glucocerebrosidase gene. We have recently shown that mutant glucocerebrosidase variants present variable degrees of endoplasmic reticulum (ER) retention and undergo ER associated degradation (ERAD) in the proteasomes. The degree of ERAD is one of the factors that determine GD severity. In order to define what factors affect the ERAD process of glucocerebrosidase in GD, we focused on two brothers with GD, carrying the same mutations but presenting extremely different clinical manifestations. One is mildly affected while the other developed severe GD with nervous system complications. Our results strongly indicated that both brothers presented variable degrees of ERAD, which was more extensive in the severely affected brother. Measurement of cholesterol demonstrated high intracellular levels in cells that derived from the severely affected brother. Growing the cells in cholesterol depleted medium led to lessening in the degree of ERAD in cells that derived from the severely affected brother and thus to improvement in stabilization, maturation, lysosomal localization and activity of the mutant glucocerebrosidase variants. The same effect was achieved by treating the cells with the HMG CoA reductase inhibitor mevastatin. None of the treatments had a significant effect on glucocerebrosidase properties in normal cells or in cells that derived from the mildly affected brother, indicating that intracellular cholesterol is one of the factors that affect the ERAD process of glucocerebrosidase and may influence the severity of GD.
- Gaucher disease