The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders.
Mutations in the gene encoding glucocerebrosidase (GBA), the enzyme deficient in the lysosomal storage disorder Gaucher disease, are associated with the development of Parkinson disease and other Lewy body disorders. In fact, GBA variants are currently the most common genetic risk factor associated with parkinsonism, and identified subjects with Parkinson disease are more than five times more likely to carry mutations in GBA. The mechanisms underlying this association are not known, but proposed theories include enhanced protein aggregation, alterations in lipid levels, and autophagy-lysosomal dysfunction promoting the retention of undegraded proteins. We review the genetic studies linking GBA to parkinsonism, as well as several of the mechanisms postulated to explain the association of GBA mutations and the synucleinopathies, which demonstrate how studies of a rare mendelian disease may provide insights into our understanding of a common complex disorder.
Velayati
Arash
A
Section on Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35, 35 Convent Drive, MSC 3708, Bethesda, MD 20892, USA.
Yu
W Haung
WH
Sidransky
Ellen
E
D000818:Animals; D020022:Genetic Predisposition to Disease; D005962:Glucosylceramidase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D020961:Lewy Body Disease / Q000201:enzymology / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*
D005962:Glucosylceramidase