Introduction: The association between
Gaucher disease, caused by the inherited deficiency of
glucocerebrosidase, and
Parkinson's disease was first recognized in the clinic, noting that patients with
Gaucher disease and their carrier relatives had an increased incidence of
Parkinson's disease. Currently, mutations in
glucocerebrosidase (GBA1) are the most common genetic risk factor for
Parkinson's disease and
dementia with Lewy bodies, with an inverse relationship between
glucocerebrosidase and α-
synuclein, a key factor in Parkinson pathogenesis. The hypothesis that therapeutic enhancement of brain
glucocerebrosidase levels might reduce the aggregation, accumulation or spread of α-
synuclein has spurred great interest in
glucocerebrosidase as a novel therapeutic target.Area covered: This article explores the potential molecular mechanisms underlying the association between GBA1 mutations and
Parkinson's disease and outlines therapeutic strategies to increase brain
glucocerebrosidase, including gene therapy, targeted delivery of recombinant
glucocerebrosidase to the brain, small-molecule chaperones to rescue mutant
glucocerebrosidase, and small-molecule modulators to activate wild-type
glucocerebrosidase.Expert opinion: Although an improved understanding of the mechanistic basis for GBA1-associated
parkinsonism is essential, enhancing levels of brain
glucocerebrosidase may have wide therapeutic implications. While gene therapy may ultimately be effective, less expensive and invasive small-molecule non-inhibitory chaperones or activators could significantly impact the disease course.