Abstract

Prion diseases are transmissible and incurable neurodegenerative disorders of humans and animals. Similar to other neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, prion diseases are characterized by protein aggregation in the central nervous system (CNS). The key molecular event in prion disease is the conformational conversion of the cellular prion protein, PrPC, into a misfolded and aggregated conformer, PrPSc, which templates further PrPC misfolding [1]. Although this same protein misfolding event occurs in all prion diseases, affected individuals expressing identical PrPC sequences can exhibit strikingly heterogeneous clinical and pathological phenotypes. These phenotypic differences have been linked to distinct PrPSc conformations, known as strains, yet the source of prion strain diversity is incompletely understood. One potential contributor to strain diversity lies in the posttranslational modifications (PTMs) on PrPC, which add a layer of structural complexity to an otherwise highly conserved protein. PrPC is posttranslationally modified by the covalent linkage of (i) 0 to 2 N-linked glycans at positions 181 and 197 (human PrP) and (ii) a glycosylphosphatidylinositol (GPI) moiety, which anchors PrPC in the outer leaflet of the plasma membrane [2,3]. The N-linked glycans on PrPC are branched [bi- (51%), tri- (32%), or tetra-antennary (17%)] and terminally sialylated, predominantly via alpha 2,6 linkages [4–6]. While necessary for regulating protein interactions and function, PTMs can profoundly modulate the pathogenesis of neurodegenerative diseases. For example, aberrant hyperphosphorylation of tau protein leads to tau detachment from microtubules and fibrillization into neurofibrillary tangles, a pathologic hallmark of Alzheimer’s disease. Prion diseases are no different, and the presence of PrP PTMs can markedly alter both the disease phenotype and transmission barrier. Here we explore how PrP PTMs impact prion conversion, cross-species transmission, the neuroinflammatory response, and PrP interaction with cofactors.

Highlights

  • Prion diseases are transmissible and incurable neurodegenerative disorders of humans and animals

  • Similar to other neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, prion diseases are characterized by protein aggregation in the central nervous system (CNS)

  • One potential contributor to strain diversity lies in the posttranslational modifications (PTMs) on PrPC, which add a layer of structural complexity to an otherwise highly conserved protein

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Summary

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Citation: Aguilar-Calvo P, Callender JA, Sigurdson CJ (2021) Short and sweet: How glycans impact prion conversion, cofactor interactions, and crossspecies transmission. PLoS Pathog 17(1): e1009123. https://doi.org/10.1371/journal. ppat.1009123 Funding: This work was supported by the National Institutes of Health grants NS069566, NS076896, NS110409, and NS105498 (CJS), AG061251 (PAC), and HL141956 (JAC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.

Introduction
How do PrP PTMs impact neuroinflammation in prion disease?
Findings
How do PrP PTMs impact interaction with cofactors?
Full Text
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