Heterozygous mutations in the GBA1 gene--which encodes for lysosomal glucocerebrosidase (GCase)--are the most common genetic risk factor for Parkinson’s disease (PD). In addition, decreased GCase activity has been reported in both genetic and sporadic cases of PD and experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a better understanding of the relationship between aSyn and GCase activity, The Michael J. Fox Foundation (MJFF) has developed and characterized two models that investigate aSyn pathology in the context of reduced GCase activity. The first model analyzes the neurodegeneration/pathology induced through constitutive overexpression of wild type human alpha-synuclein directed by the murine Thy-1 promoter (hemizygous transgenic) in the context of the GCase activity-reducing D409V mutant form of GBA (homozygous knockin). The second model analyzes the level of nigrostriatal degeneration and synuclein pathology in the GBA D409V knockin model versus wildtype mice following injection of aSyn preformed fibrils into the striatum. Herein we discuss the results of these model characterization efforts. Understanding the potential synergistic effect of increased aSyn and decreased GCase activity is important for the understanding how alterations in GCase activity may contribute to or exacerbate PD-related pathology and provide important platforms for testing therapeutics looking to intervene in this pathway/relationship.