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B. CASEY1, N. POLINSKI1, T. N. MARTINEZ1, S. W. CLARK2, S. M. SMITH3, R. C. SWITZER III4, S. O. AHMAD5, S. RAMBOZ6, M. SASNER7, M. T. HERBERTH8, L. MENALLED1, M. A. BAPTISTA1, K. D. DAVE1, M. FRASIER1


1The Michael J. Fox Fndn., New York, NY; 2Amicus Therapeut., Cranbury, NJ; 3Merck Res. Labs., West Point, PA; 4Neurosci. Associates Inc, Knoxville, TN; 5Doisy Hlth. Sciences: Office of Occup. Therapy, St. Louis Univ., Saint Louis, MO; 6Psychogenics Inc., Paramus, NJ; 7The Jackson Lab., Bar Harbor, ME; 8Charles River, Ashland, OH.


Heterozygous mutations in the GBA1 gene, which encodes 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. Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). Thus, understanding the potential synergistic effect of increased aSyn and decreased GCase activity is important for understanding how alterations in GCase activity may contribute to or exacerbate PD-related pathology. To enable a better understanding of the relationship between aSyn and GCase activity, The Michael J. Fox Foundation (MJFF) has developed and characterized two mouse models allowing investigation of 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 stereotaxic injection of aSyn preformed fibrils into the striatum. Here, we outline and discuss the results of these model characterization efforts. Together, these models provide important platforms for understanding the mechanisms underlying GCase and aSyn dynamics, and for evaluating therapeutics targeting this pathway/relationship.