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    Posttranslational modifications define course of prion strain adaptation and disease phenotype

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    Author
    Makarava, Natallia
    Chang, Jennifer Chen-Yu
    Molesworth, Kara
    Baskakov, Ilia V
    Date
    2020-08-03
    Journal
    Journal of Clinical Investigation
    Publisher
    American Society of Clinical Oncology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/JCI138677
    Abstract
    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.
    Keyword
    Infectious disease
    Innate immunity
    Neurodegeneration
    Neuroscience
    Prions
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13559
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI138677
    Scopus Count
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    UMB Open Access Articles 2020

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