| First Author | Holec SAM | Year | 2022 |
| Journal | PLoS Pathog | Volume | 18 |
| Issue | 12 | Pages | e1010956 |
| PubMed ID | 36454879 | Mgi Jnum | J:336065 |
| Mgi Id | MGI:7410414 | Doi | 10.1371/journal.ppat.1010956 |
| Citation | Holec SAM, et al. (2022) The E46K mutation modulates alpha-synuclein prion replication in transgenic mice. PLoS Pathog 18(12):e1010956 |
| abstractText | In multiple system atrophy (MSA), the alpha-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration. While the E46K mutation in alpha-synuclein causes familial Parkinson's disease (PD), we previously discovered that this mutation blocks in vitro propagation of MSA prions. Recent studies by others indicate that alpha-synuclein adopts a misfolded conformation in MSA in which a Greek key motif is stabilized by an intramolecular salt bridge between residues E46 and K80. Hypothesizing that the E46K mutation impedes salt bridge formation and, therefore, exerts a selective pressure that can modulate alpha-synuclein strain propagation, we asked whether three distinct alpha-synuclein prion strains could propagate in TgM47+/- mice, which express human alpha-synuclein with the E46K mutation. Following intracranial injection of these strains, TgM47+/- mice were resistant to MSA prion transmission, whereas recombinant E46K preformed fibrils (PFFs) transmitted neurological disease to mice and induced the formation of phosphorylated alpha-synuclein neuropathology. In contrast, heterotypic seeding following wild-type (WT) PFF-inoculation resulted in preclinical alpha-synuclein prion propagation. Moreover, when we inoculated TgM20+/- mice, which express WT human alpha-synuclein, with E46K PFFs, we observed delayed transmission kinetics with an incomplete attack rate. These findings suggest that the E46K mutation constrains the number of alpha-synuclein prion conformations that can propagate in TgM47+/- mice, expanding our understanding of the selective pressures that impact alpha-synuclein prion replication. |
