Dataset Information

Glial activation in prion diseases is selectively triggered by neuronal PrP^Sc.

ABSTRACT: Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrP^C selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron-restricted PrP^C expression led to copious brain accumulation of PrP^Sc . As expected, neuron-restricted expression was associated with typical prion disease. However, mice with astrocyte-restricted PrP^C expression experienced a normal life span, did not develop clinical disease, and did not show astro- or microgliosis. Besides confirming that PrP^Sc is innocuous to PrP^C -deficient neurons, these results show that astrocyte-born PrP^Sc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion-infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction.

SUBMITTER: Lakkaraju AKK

PROVIDER: S-EPMC9425016 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Glial activation in prion diseases is selectively triggered by neuronal PrPSc.

Lakkaraju Asvin K K AKK Sorce Silvia S Senatore Assunta A Nuvolone Mario M Guo Jingjing J Schwarz Petra P Moos Rita R Pelczar Pawel P Aguzzi Adriano A

Brain pathology (Zurich, Switzerland) 20220217 5

Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrPC selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron-restricted PrPC expression led to copious brain accumulation of PrPSc . As expected, neuron-restricted expression was associated with typical ...[more]

PMID: 35178783

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

Glial activation in prion diseases is selectively triggered by neuronal PrP^Sc.

Publications

Glial activation in prion diseases is selectively triggered by neuronal PrP<sup>Sc</sup>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets