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Mutations in  GBA1 , the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies. A higher prevalence and increased severity of motor and non-motor symptoms is observed in PD patients harboring mutant  GBA1  alleles, suggesting a link between the gene or gene product and disease development. Interestingly, PD patients without mutations in  GBA1  also exhibit lower levels of glucocerebrosidase activity in the central nervous system (CNS), implicating this lysosomal enzyme in disease pathogenesis. Here, we investigated whether modulation of glucocerebrosidase activity in murine models of synucleinopathy (expressing wild type  Gba1 ) affected α-synuclein accumulation and behavioral phenotypes. Partial inhibition of glucocerebrosidase activity in  PrP-A53T-SNCA  mice using the covalent inhibitor conduritol-B-epoxide induced a profound increase in soluble α-synuclein in the CNS and exacerbated cognitive and motor deficits. Conversely, augmenting glucocerebrosidase activity in the  Thy1-SNCA  mouse model of PD delayed the progression of synucleinopathy. Adeno-associated virus-mediated expression of glucocerebrosidase in the  Thy1-SNCA  mouse striatum led to decrease in the levels of the proteinase K-resistant fraction of α-synuclein, amelioration of behavioral aberrations and protection from loss of striatal dopaminergic markers. These data indicate that increasing glucocerebrosidase activity can influence α-synuclein homeostasis, thereby reducing the progression of synucleinopathies. This study provides robust  in vivo  evidence that augmentation of CNS glucocerebrosidase activity is a potential therapeutic strategy for PD, regardless of the mutation status of  GBA1 .

Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinson’s disease