Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease.
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.
a Section on Molecular Neurogenetics, Medical Genetics Branch , National Human Genome Research Institute, NIH , Bethesda , MD , USA.
Olive
O
Jung
b National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , MD , USA.
Samarjit
S
Patnaik
b National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , MD , USA.
Juan
J
Marugan
a Section on Molecular Neurogenetics, Medical Genetics Branch , National Human Genome Research Institute, NIH , Bethesda , MD , USA.
Ellen
E
Sidransky
a Section on Molecular Neurogenetics, Medical Genetics Branch , National Human Genome Research Institute, NIH , Bethesda , MD , USA.
Wendy
W
Westbroek
D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology; D005962:Glucosylceramidase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D051843:Synucleins / Q000187:drug effects / Q000235:genetics
D051843:Synucleins; D005962:Glucosylceramidase
Gaucher disease; Lysosomal storage diseases; Parkinson disease; chemical chaperone; glucocerebrosidase; high throughput screening; synculeinopathies