Posttranslational modifications define course of prion strain adaptation and disease phenotype

Introduction Prion diseases are a group of fatal neurodegenerative diseases of humans and other mammals that can arise spontaneously or via transmission (1). The transmissible agent of prion disease consists [...]
Posttranslational modifications are a common feature of proteins associated with neurodegenerative diseases including prion protein ([PrP.sup.C]), tau, and a-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 [PrP.sup.C] sialoglycoforms expressed by a cell, individual prion strains recruited [PrP.sup.C] 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 [PrP.sup.C] sialoglycoforms, giving rise to a self-propagating scrapie isoform ([PrP.sup.Sc]) 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 [PrP.sup.Sc] with microglia and a very profound proinflammatory response, features that are linked to a unique sialoglycoform composition of [PrP.sup.Sc]. The current work provides experimental support for the hypothesis that strain-specific patterns of [PrP.sup.Sc] 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.