ABSTRACT

Gaucher disease (GD), an inherited lysosomal storage disorder characterized by impaired activity of the lysosomal enzyme β-glucocerebrosidase (GCase), results from mutations in the corresponding GBA gene. Due to the impaired activity of mutant GCase, there is accumulation of lysosomal glucosylceramide, which ultimately leads to lysosomal dysfunction (Beutler 1980, Beutler and Dale 1982, Brady 1982, Beutler and Gelbart 1996, Beutler 1999). Due to its heterogeneity, GD was divided into three types: type 1, primarily a non-neurological disease; type 2, the acute neuronopathic disease; and type 3, the sub-acute neuronopathic disease (Hruska et al. 2008). The hallmark of GD is reduced lysosomal GCase activity and elevation in glucosylceramide levels mainly in monocyte derived cells. The reduced lysosomal GCase activity refl ects the fact that mutant GCase variants are recognized in the endoplasmic reticulum ER as misfolded, and are retained there by the ER quality control machinery, in an attempt to correctly fold the mutant molecules. This ER retention leads to ER stress and eventually to ER stress response, known as the unfolded protein response (UPR), and ER associated degradation (ERAD) (Kono et al. 2010), which involves retrotranslocation of the mutant molecules through the ER membrane into the cytosol where they undergo ubiquitination and proteasomal degradation. The level of ERAD is directly correlated to disease severity (Ron and Horowitz 2005, Mu et al. 2008, Maor et al. 2013).