Parkinson disease (PD) is a neurodegenerative disease affecting at least 1 million people in the U.S. and it has been estimated that 14.6 million people will be affected worldwide by 2040. Pathologic intraneuronal inclusions composed of misfolded ?-synuclein accumulate in Lewy bodies and Lewy neurites, resulting in progressive degeneration within the periphery and across the neuraxis including the of the nigrostriatal system which mediates the cardinal symptoms of the disease. Because of disease heterogeneity, before therapeutic strategies can be fairly tested, it is critical to identify and examine specific subtypes of PD, as different forms of PD are likely to have both distinct and overlapping pathogenic mechanisms. Mutations in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for PD. Clinically, GBA mutation carriers with PD have more aggressive motor decline and develop dementia faster than non-mutation carriers with PD. In parallel, PD subjects with GBA mutations also have a more rapid accumulation and spread of ?- synuclein. The relationship between GBA mutations, rapid and both motor and non-motor decline, and this wide-spread ?-synuclein accumulation, remains to be clearly elucidated and its understanding will likely related to sporadic PD as well. This application aims to define whether the aggressive pathologic and motor phenotype of GBA mutation carriers with PD is due to: 1) reduced host GCase enzymatic activity and/or 2) specific strains of aggregated ?-synuclein unique to GBA mutation carriers result in enhanced ?-synuclein propagation and functional motor progression in a GBA mouse model.
In aim 1, we will determine whether there is more aggressive alpha-syn propagation and more aggressive functional decline in a Gba1D409V/D409V mouse model compared with wild-type mice. This mutant mouse model, like GBA mutation carriers with PD, has reduced GCase enzymatic activity. We hypothesize that wild-type HuPFF injection into the OB in Gba1D409V/D409V mice will have increased ?-synuclein propagation and functional motor and cognitive progression compared with wild-type mice.
In aim 2, we will compare the effect of GBA vs. WT PFFs on structural and functional progression of alpha-syn pathology in wild-type mice. We hypothesize that GBA PFF injection into the OB in wild-type mice will result in increased ?-synuclein propagation and functional motor and cognitive progression compared with wild-type PFF injections. We are uniquely equipped to test this hypothesis as our lab has done critical work in demonstrating transneuronal ?-synuclein propagation. The rationale for the proposed research is that once we determine the mechanism of ?-synuclein propagation and functional motor and cognitive progression in our model, we will apply this knowledge toward novel treatments to prevent ?-synuclein propagation for GBA associated PD. The proposed research will also open the door to new research aimed at understanding how ?-synuclein strains contribute to the diverse pathological and clinical presentations of a variety of ?-synucleinopathies, including PD, MSA, and DLB.
Mutations in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for PD and Clinically, GBA mutation carriers with PD have more aggressive motor decline, develop dementia faster than non-mutation carriers with PD (Winder-Rhodes 2013), and have a more rapid accumulation and spread of ?- synuclein. This application aims to define whether the aggressive pathologic and motor phenotype of GBA mutation carriers with PD is due to: 1) reduced host GCase enzymatic activity and/or 2) specific strains of aggregated ?-synuclein unique to GBA mutation carriers which result in enhanced ?-synuclein propagation and functional motor progression in a GBA mouse model.
