The association between ß-glucocerebrosidase mutations and parkinsonism

Abstract

Mutations in the ß-glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme ß-glucocerebrosidase, have traditionally been implicated in Gaucher disease, an autosomal recessive lysosomal storage disorder. Yet the past two decades have yielded an explosion of epidemiological and basic-science evidence linking mutations in GBA with the development of Parkinson disease (PD) as well. Although the specific contribution of mutant GBA to the pathogenesis of parkinsonism remains unknown, evidence suggests that both loss of function and toxic gain of function by abnormal ß-glucocerebrosidase may be important, and implicates a close relationship between ß-glucocerebrosidase and α-synuclein. Furthermore, multiple lines of evidence suggest that although GBA-associated PD closely mimics idiopathic PD (IPD), it may present at a younger age, and is more frequently complicated by cognitive dysfunction. Understanding the clinical association between GBA and PD, and the relationship between ß-glucocerebrosidase and α-synuclein, may enhance understanding of the pathogenesis of IPD, improve prognostication and treatment of GBA carriers with parkinsonism, and furthermore inform therapies for IPD not due to GBA mutations.

Figure 1

The complex genetics of GBA-related Parkinson disease (PD). Most PD-related genes have fairly clear autosomal dominant (LRRK2) or autosomal recessive (ATP13A2, DJ1) inheritance. Certain genes (Parkin, PINK1) are largely autosomal recessive, although disease may be present in the heterozygous state. GBA is even more complex genetic: “mild” mutations could be considered risk factors for PD, or else autosomal dominant PD genes with a low penetrance; more “severe” mutations could be considered either stronger risk factors for PD, or autosomal dominant PD genes with a higher penetrance; and heterozygosity for two GBA mutations results in Gaucher disease (GD), type 1 of which carries an increased risk of developing PD. The relationship of GBA mutations to PD thus confounds the classical paradigm of monogenic disorders.