α-Synuclein Strain Propagation is Independent of Cellular Prion Protein Expression in Transgenic Mice

Abstract

AbstractThe cellular prion protein, PrPC, 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. To test this hypothesis, we compared the propagation behavior of two different α-synuclein aggregate strains in M83 transgenic mice that either expressed or did not express PrPC. Following intracerebral inoculation with the S or NS strain, the presence of PrPChad minimal influence on α-synuclein strain-specified attributes such as the kinetics of disease progression, 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 PrPC-expressing and PrPC-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 PrPCexpression. Overall, these results suggest that PrPCplays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains. Thus, other putative receptors or cell-to-cell propagation mechanisms may play a larger role in the spread of α-synuclein aggregates during disease.