The E46K mutation modulates α-synuclein prion replication in transgenic mice.
Autor: | Sara A M Holec, Jisoo Lee, Abby Oehler, Lyn Batia, Aryanna Wiggins-Gamble, Jeffrey Lau, Felicia K Ooi, Gregory E Merz, Man Wang, Daniel A Mordes, Steven H Olson, Amanda L Woerman |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: | |
Zdroj: | PLoS Pathogens, Vol 18, Iss 12, p e1010956 (2022) |
Druh dokumentu: | article |
ISSN: | 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1010956 |
Popis: | In multiple system atrophy (MSA), the α-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration. While the E46K mutation in α-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 α-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 α-synuclein strain propagation, we asked whether three distinct α-synuclein prion strains could propagate in TgM47+/- mice, which express human α-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 α-synuclein neuropathology. In contrast, heterotypic seeding following wild-type (WT) PFF-inoculation resulted in preclinical α-synuclein prion propagation. Moreover, when we inoculated TgM20+/- mice, which express WT human α-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 α-synuclein prion conformations that can propagate in TgM47+/- mice, expanding our understanding of the selective pressures that impact α-synuclein prion replication. |
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