α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model

The cellular prion protein, PrP$^{C}$, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson’s disease. Previously, we generated the “Salt (S)” and “No Salt (NS)” strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrP$^{C}$ facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrP$^{C}$. Following intracerebral inoculation with the S or NS strain, the absence of PrP$^{C}$ in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrP$^{C}$-expressing and PrP$^{C}$-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrP$^{C}$ expression. Overall, these results suggest that PrP$^{C}$ plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.