The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders

Abstract

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.

Fig. 1

Frequency of GBA mutation carriers among patients with Parkinson disease and the distribution of different mutations in Ashkenazi Jews and non-Ashkenazi ethnic populations. A Twenty percent of Ashkenazi Jewish patients were found to carry a GBA mutation. B Among non-Ashkenazi Jewish patients for whom full sequencing was performed, 6.5% carried GBA mutations (from a meta-analysis by Sidransky et al. [36••]). The data in panel B are summarized based on whole GBA sequencing in three studies (Sidransky et al., 2009 [36••]; Neumann et al., 2009 [31•]; and Kalinderi et al., 2009 [33]). “Other alleles” include K(-27)R, K7E, R32H, R39H, R44C, R131C, R131S, D140H, R163Q, R163X, G193E, G193W, K198T, F213I, F216Y, R239C, R257Q, R262H, L268L, S271G, T323I, E326K, R329C, L336P, G344S, N370K, L371I, D380N, D380A, D443N, V460M, T482K, R496C, Q497R, c.1263-1317 del55bp, RecA456P, and RecNcil