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bioRxiv · 10.1101/2024.03.27.587028

α-Synuclein strain propagation is independent of cellular prion protein expression in transgenic mice

So, R. W. L.·Stuart, E.·Amini, A. E.·Aguzzi, A.·Collingridge, G. L.·Watts, J. C.
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Abstract

The cellular prion protein, PrPC, has been postulated to function as a receptor for -synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of -synuclein aggregates in neurodegenerative disorders such as Parkinsons disease. To test this hypothesis, we compared the propagation behavior of two different -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 PrPC had minimal influence on -synuclein strain-specified attributes such as the kinetics of disease progression, the extent of cerebral -synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced -synuclein deposits, and the structural fingerprints of protease-resistant -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 -synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of -synuclein strains. Thus, other putative receptors or cell-to-cell propagation mechanisms may play a larger role in the spread of -synuclein aggregates during disease.

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So, R. W. L., Stuart, E., Amini, A. E., Aguzzi, A., Collingridge, G. L., Watts, J. C.. 2024-03-30. α-Synuclein strain propagation is independent of cellular prion protein expression in transgenic mice. https://doi.org/10.1101/2024.03.27.587028

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