Chaperoning glucocerebrosidase: a therapeutic strategy for both Gaucher disease and Parkinsonism.

Abstract

Gaucher disease (GD) is a lysosomal storage disorder (LSD) affecting approximately 1 in 50,000 individuals in the general population. Mutations in both alleles of the GBA1 gene result in deficient glucocerebrosidase (GCase) activity, which in turn leads to the accumulation of glycolipid substrates and impaired lysosomal function. GD is a multisystem disorder with a vast spectrum of clinical phenotypes, including both non-neuronopathic type 1 Gaucher disease (GD1) and neuronopathic types 2 and 3 Gaucher disease (GD2 and GD3). In addition to its role in the rare disorder GD, mutations in GBA1 are the most frequent known genetic risk factor for the common complex disorder Parkinson's disease (PD) (Sidransky et al., 2009). Depending on ethnicity, patients with Parkinson's disease are 2–31% more likely to carry a mutation in GBA1 than matched controls (Sidransky and Lopez, 2012). There appears to be a reciprocal relationship between levels of GCase and levels of the aggregate-prone protein alpha-synuclein (Mazzulli et al., 2011; Murphy and Halliday, 2014). Thus therapies focused on increasing GCase, especially in the brain, have attracted increased attention. To enhance the development of new therapeutics targeting GCase, attention has turned toward induced human pluripotent stem cell (iPSC)-derived models of GD (Aflaki et al., 2014). These new patient-derived models can be used to test the efficacy of new therapeutic strategies. Very recently, two novel small-molecule non-inhibitory chaperones of GCase were evaluated in such models with promising results (Aflaki et al., 2014, 2016; Mazzulli et al., 2016). The findings may pave the way for pharmacological development relevant to both GD and Parkinson's disease