Posttranslational modifications define course of prion strain adaptation and disease phenotype
Date
2020-08-03Journal
Journal of Clinical InvestigationPublisher
American Society of Clinical OncologyType
Article
Metadata
Show full item recordAbstract
Posttranslational modifications are a common feature of proteins associated with neurodegenerative diseases including prion protein (PrPC), tau, and α-synuclein. Alternative self-propagating protein states or strains give rise to different disease phenotypes and display strain-specific subsets of posttranslational modifications. The relationships between strain-specific structure, posttranslational modifications, and disease phenotype are poorly understood. We previously reported that among hundreds of PrPC sialoglycoforms expressed by a cell, individual prion strains recruited PrPC molecules selectively, according to the sialylation status of their N-linked glycans. Here we report that transmission of a prion strain to a new host is accompanied by a dramatic shift in the selectivity of recruitment of PrPC sialoglycoforms, giving rise to a self-propagating scrapie isoform (PrPSc) with a unique sialoglycoform signature and disease phenotype. The newly emerged strain has the shortest incubation time to disease and is characterized by colocalization of PrPSc with microglia and a very profound proinflammatory response, features that are linked to a unique sialoglycoform composition of PrPSc. The current work provides experimental support for the hypothesis that strain-specific patterns of PrPSc sialoglycoforms formed as a result of selective recruitment dictate strain-specific disease phenotypes. This work suggests a causative relationship between a strain-specific structure, posttranslational modifications, and disease phenotype.Identifier to cite or link to this item
http://hdl.handle.net/10713/13559ae974a485f413a2113503eed53cd6c53
10.1172/JCI138677
Scopus Count
Collections
Related articles
- Cofactor and glycosylation preferences for in vitro prion conversion are predominantly determined by strain conformation.
- Authors: Burke CM, Walsh DJ, Mark KMK, Deleault NR, Nishina KA, Agrimi U, Di Bari MA, Supattapone S
- Issue date: 2020 Apr
- Region-Specific Sialylation Pattern of Prion Strains Provides Novel Insight into Prion Neurotropism.
- Authors: Makarava N, Chang JC, Baskakov IV
- Issue date: 2020 Jan 28
- Prion replication environment defines the fate of prion strain adaptation.
- Authors: Katorcha E, Gonzalez-Montalban N, Makarava N, Kovacs GG, Baskakov IV
- Issue date: 2018 Jun
- Sialylation of prion protein controls the rate of prion amplification, the cross-species barrier, the ratio of PrPSc glycoform and prion infectivity.
- Authors: Katorcha E, Makarava N, Savtchenko R, D'Azzo A, Baskakov IV
- Issue date: 2014 Sep
- Non-genetic propagation of strain-specific properties of scrapie prion protein.
- Authors: Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B
- Issue date: 1995 Jun 22