Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease

Abstract

Gaucher disease, caused by pathological mutations GBA1, encodes the lysosome-resident enzyme glucocerebrosidase, which cleaves glucosylceramide into glucose and ceramide. In Gaucher disease, glucocerebrosidase deficiency leads to lysosomal accumulation of substrate, primarily in cells of the reticulo-endothelial system. Gaucher disease has broad clinical heterogeneity, and mutations in GBA1 are a risk factor for the development of different synucleinopathies. Insights into the cell biology and biochemistry of glucocerebrosidase have led to new therapeutic approaches for Gaucher disease including small chemical chaperones. Such chaperones facilitate proper enzyme folding and translocation to lysosomes, thereby preventing premature breakdown of the enzyme in the proteasome. This review discusses recent progress in developing chemical chaperones as a therapy for Gaucher disease, with implications for the treatment of synucleinopathies. It focuses on the development of non-inhibitory glucocerebrosidase chaperones and their therapeutic advantages over inhibitory chaperones, as well as the challenges involved in identifying and validating chemical chaperones.

Keywords: Gaucher disease; Lysosomal storage diseases; Parkinson disease; chemical chaperone; glucocerebrosidase; high throughput screening; synculeinopathies.

Figure 1

Non-inhibitory chaperones for enhancement of GCase. (A) Wild-type GCase is folded in the ER and translocated to lysosomes where it turns over its substrate. (B) Mutant GCase is misfolded in the ER and undergoes premature degradation in the proteasome with subsequent lysosomal accumulation. (C) Non-inhibitory chaperones facilitate folding and stabilization of mutant GCase in the ER as well as translocation to lysosomes where the residual activity of mutant enzyme is able to turn over substrate.

Figure 2

(A) Inhibitory chaperones bind to the active site of mutant GCase. Once the enzyme-inhibitor complex reaches lysosomes, the inhibitor should be out-competed by accumulating substrate. (B) Non-inhibitory chaperones do not bind to the active site of mutant GCase. Substrate binding in the active site of the enzyme can happen without competition.