Prion diseases are transmissible neurodegenerative maladies that are caused by misfolding and aggregation of the prion protein and display diverse disease phenotypes. Regardless of a disease phenotype, chronic inflammation of the glia is considered to be central to disease pathogenesis. The diversity of disease phenotypes is attributed to the ability of normal form of the prion protein or PrPC to misfold into multiple, structurally distinct, self-replicating PrPSc states referred to as prion strains or subtypes. The question of how different PrPSc structures elicit diverse pathological response by CNS remains poorly understood. In fact, the relationship between strain-specific PrPSc structures and CNS responses remains empirical, whereas a mechanism that would describe their relationship in a predictable manner is lacking. Moreover, it remains unclear what molecular features of PrPSc are responsible for chronic inflammation and neurodegeneration. Lack of this knowledge represents a key gap in the field. The current application proposes a novel mechanism, according to which carbohydrate epitopes formed by N- linked glycans on PrPSc surface determine strain-specific response of CNS. The key element of this new mechanism is a selective recruitment of PrPC glycoforms by PrPSc, which is governed by strain-specific PrPSc structures and results in strain-specific patterns of carbohydrate epitopes on PrPSc surface. As a part of this mechanism, we propose that deposition of PrPSc triggers phenotypic changes in glia, where the resulting glial phenotypes are determined by the patterns of carbohydrate epitopes on PrPSc surface. For rigorous testing of above mechanism, we developed biochemical approaches for manipulating PrPSc carbohydrate patterns in vitro, and generated new PrPSc states with unique glycosylation status in animals.
Aim 1 will test whether PrPC glycoforms are recruited into PrPSc selectively and in a strain-specific manner.
Aim 2 will examine a relationship between PrPSc carbohydrate epitopes and activation states of glia, whereas Aim 3 will elucidate molecular features of PrPSc responsible for inflammation and neurodegeneration. Multidisciplinary approaches, including animal pathology, primary cell cultures, mass spectrometry and biochemical techniques, will be employed to elucidate the mechanisms behind chronic inflammation and neurodegeneration. This study will provide a rigorous test of the new hypothesis on the role of PrPSc carbohydrate epitopes in determining functional states of glia. When the project is completed, a comprehensive picture of the role of N-linked glycans in prion diseases will emerge. It is anticipated that this study will lead to new targets for therapeutic intervention against prion diseases.
Chronic inflammation and neurodegeneration are key pathological hallmarks of prion and other age- dependent neurodegenerative diseases. In prion diseases, chronic inflammation of the glia is considered to be central to disease pathogenesis. The current work will test a new hypothesis that alterations of the local carbohydrate environment in CNS due to deposition of prion aggregates trigger diverse response programs in glia, and that the type of response and the resulting glial phenotypes are determined by the patterns of carbohydrate epitopes on the surface of prion aggregates.
| Srivastava, Saurabh; Katorcha, Elizaveta; Makarava, Natallia et al. (2018) Inflammatory response of microglia to prions is controlled by sialylation of PrPSc. Sci Rep 8:11326 |
| Katorcha, Elizaveta; Gonzalez-Montalban, Nuria; Makarava, Natallia et al. (2018) Prion replication environment defines the fate of prion strain adaptation. PLoS Pathog 14:e1007093 |
| Katorcha, Elizaveta; Baskakov, Ilia V (2018) Analysis of Covalent Modifications of Amyloidogenic Proteins Using Two-Dimensional Electrophoresis: Prion Protein and Its Sialylation. Methods Mol Biol 1779:241-255 |
| Makarava, Natallia; Savtchenko, Regina; Lasch, Peter et al. (2018) Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein. Acta Neuropathol Commun 6:92 |
| Makarava, Natallia; Savtchenko, Regina; Baskakov, Ilia V (2017) Purification and Fibrillation of Full-Length Recombinant PrP. Methods Mol Biol 1658:3-22 |
| Baskakov, Ilia V (2017) Limited understanding of the functional diversity of N-linked glycans as a major gap of prion biology. Prion 11:82-88 |
| Srivastava, Saurabh; Katorcha, Elizaveta; Daus, Martin L et al. (2017) Sialylation Controls Prion Fate in Vivo. J Biol Chem 292:2359-2368 |
| Makarava, Natallia; Savtchenko, Regina; Baskakov, Ilia V (2017) Methods of Protein Misfolding Cyclic Amplification. Methods Mol Biol 1658:169-183 |
| Katorcha, Elizaveta; Baskakov, Ilia V (2017) Analyses of N-linked glycans of PrPSc revealed predominantly 2,6-linked sialic acid residues. FEBS J 284:3727-3738 |
| Katorcha, Elizaveta; Daus, Martin L; Gonzalez-Montalban, Nuria et al. (2016) Reversible off and on switching of prion infectivity via removing and reinstalling prion sialylation. Sci Rep 6:33119 |
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