In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 12 ( 2022-12-1), p. e1010956-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010956
DOI:
10.1371/journal.ppat.1010956.g001
DOI:
10.1371/journal.ppat.1010956.g002
DOI:
10.1371/journal.ppat.1010956.g003
DOI:
10.1371/journal.ppat.1010956.g004
DOI:
10.1371/journal.ppat.1010956.g005
DOI:
10.1371/journal.ppat.1010956.g006
DOI:
10.1371/journal.ppat.1010956.t001
DOI:
10.1371/journal.ppat.1010956.t002
DOI:
10.1371/journal.ppat.1010956.t003
DOI:
10.1371/journal.ppat.1010956.t004
DOI:
10.1371/journal.ppat.1010956.t005
DOI:
10.1371/journal.ppat.1010956.s001
DOI:
10.1371/journal.ppat.1010956.s002
DOI:
10.1371/journal.ppat.1010956.s003
DOI:
10.1371/journal.ppat.1010956.s004
DOI:
10.1371/journal.ppat.1010956.s005
DOI:
10.1371/journal.ppat.1010956.s006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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