Dataset Information

Inflammatory response of microglia to prions is controlled by sialylation of PrP^Sc.

ABSTRACT: Neuroinflammation is recognized as one of the obligatory pathogenic features of neurodegenerative diseases including Alzheimer's, Parkinson's or prion diseases. In prion diseases, space and time correlations between deposition of disease-associated, pathogenic form of the prion protein or PrP^Sc and microglial-mediated neuroinflammation has been established. Yet, it remains unclear whether activation of microglia is triggered directly by a contact with PrP^Sc, and what molecular features of PrP^Sc microglia sense and respond to that drive microglia to inflammatory states. The current study asked the questions whether PrP^Sc can directly trigger activation of microglia and whether the degree of microglia response depends on the nature of terminal carbohydrate groups on the surface of PrP^Sc particles. PrP^Sc was purified from brains of mice infected with mouse-adapted prion strain 22L or neuroblastoma N2a cells stably infected with 22L. BV2 microglial cells or primary microglia were cultured in the presence of purified 22L. We found that exposure of BV2 cells or primary microglia to purified PrP^Sc triggered proinflammatory responses characterized by an increase in the levels of TNFα, IL6, nitric oxide (NO) and expression of inducible Nitric Oxide Synthase (iNOS). Very similar patterns of inflammatory response were induced by PrP^Sc purified from mouse brains and neuroblastoma cells arguing that microglia response is independent of the source of PrP^Sc. To test whether the microglial response is mediated by carbohydrate epitopes on PrP^Sc surface, the levels of sialylation of PrP^Sc N-linked glycans was altered by treatment of purified PrP^Sc with neuraminidase. Partial cleavage of sialic acid residues was found to boost the inflammatory response of microglia to PrP^Sc. Moreover, transient degradation of Iκβα observed upon treatment with partially desialylated PrP^Sc suggests that canonical NFκB activation pathway is involved in inflammatory response. The current study is the first to demonstrate that PrP^Sc can directly trigger inflammatory response in microglia. In addition, this work provides direct evidence that the chemical nature of the carbohydrate groups on PrP^Sc surface is important for microglial activation.

SUBMITTER: Srivastava S

PROVIDER: S-EPMC6063910 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Prion diseases are fatal neurodegenerative diseases in mammals with the unique characteristics of misfolding and aggregation of the cellular prion protein (PrPC) to the scrapie prion (PrPSc). Although neuroinflammation and neuronal loss feature within the disease process, the details of PrPC/PrPSc molecular transition to generate different aggregated species, and the correlation between each species and sequence of cellular events in disease pathogenesis are not fully understood. In this study, using mice inoculated with the RML isolate of mouse-adapted scrapie as a model, we applied asymmetric flow field-flow fractionation to monitor PrPC and PrPSc particle sizes and we also measured seeding activity and resistance to proteases. For cellular analysis in brain tissue, we measured inflammatory markers and synaptic damage, and used the isotropic fractionator to measure neuronal loss; these techniques were applied at different timepoints in a cross-sectional study of disease progression. Our analyses align with previous reports defining significant decreases in PrPC levels at pre-clinical stages of the disease and demonstrate that these decreases become significant before neuronal loss. We also identified the earliest PrPSc assemblies at a timepoint equivalent to 40% elapsed time for the disease incubation period; we propose that these assemblies, mostly composed of proteinase K (PK)-sensitive species, play an important role in triggering disease pathogenesis. Lastly, we show that the PK-resistant assemblies of PrPSc that appear at timepoints close to the terminal stage have similar biophysical characteristics, and hence that preparative use of PK-digestion selects for this specific subpopulation. In sum, our data argue that qualitative, as well as quantitative, changes in PrP conformers occur at the midpoint of subclinical phase; these changes affect quaternary structure and may occur at the threshold where adaptive responses become inadequate to deal with pathogenic processes.

Dataset Information

Inflammatory response of microglia to prions is controlled by sialylation of PrP^Sc.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Inflammatory response of microglia to prions is controlled by sialylation of PrPSc.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Inflammatory response of microglia to prions is controlled by sialylation of PrP^Sc.