{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Holec SAM"],"funding":["National Institute of Neurological Disorders and Stroke","University of Massachusetts Amherst","Sherman Fairchild Foundation","CurePSP","Sergey Brin Foundation","National Institute on Aging"],"pagination":["e1010956"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9714912"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["18(12)"],"pubmed_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."],"journal":["PLoS pathogens"],"pubmed_title":["The E46K mutation modulates α-synuclein prion replication in transgenic mice."],"pmcid":["PMC9714912"],"funding_grant_id":["R01NS121294","668-2020-06","P01AG002132"],"pubmed_authors":["Wang M","Oehler A","Lau J","Ooi FK","Lee J","Wiggins-Gamble A","Merz GE","Olson SH","Batia L","Holec SAM","Mordes DA","Woerman AL"],"additional_accession":[]},"is_claimable":false,"name":"The E46K mutation modulates α-synuclein prion replication in transgenic mice.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2025-04-22T01:53:16.838Z","creation":"2025-04-05T20:06:52.156Z"},"accession":"S-EPMC9714912","cross_references":{"pubmed":["36454879"],"doi":["10.1371/journal.ppat.1010956"]}}