Gaucher disease.

Although Gaucher disease is a rare disorder, recent developments in novel means for therapeutic intervention have invigorated both academic research and pharmaceutical industry discovery programmes. The common mutations found in the lysosomal enzyme deficient in Gaucher disease, beta-glucocerebrosidase, earmark these proteins for destruction by the endoplasmic reticulum-localised protein folding machinery, resulting in enzyme insufficiency, lysosomal glycolipid storage and subsequent pathology. However, many of these mutants can be rescued from global misfolding to preserve glycolipid substrate binding and eventual catalysis in the lysosome, by the addition of subinhibitory concentrations of pharmacologically active small molecules. This novel, chaperon-mediated approach has benefited from insights into the molecular understanding of beta-glucocerebrosidase structure, drug design and development in cellular models for disease.