Calcineurin Controls Cellular Prion Protein Expression in Mouse Astrocytes
CELLS(2022)
Abstract
Prion diseases arise from the conformational conversion of the cellular prion protein (PrP(C)) into a self-replicating prion isoform (PrPSc). Although this process has been studied mostly in neurons, a growing body of evidence suggests that astrocytes express PrP(C) and are able to replicate and accumulate PrPSc. Currently, prion diseases remain incurable, while downregulation of PrP(C) represents the most promising therapy due to the reduction of the substrate for prion conversion. Here we show that the astrocyte-specific genetic ablation or pharmacological inhibition of the calcium-activated phosphatase calcineurin (CaN) reduces PrP(C) expression in astrocytes. Immunocytochemical analysis of cultured CaN-KO astrocytes and isolation of synaptosomal compartments from the hippocampi of astrocyte-specific CaN-KO (ACN-KO) mice suggest that PrP(C) is downregulated both in vitro and in vivo. The downregulation occurs without affecting the glycosylation of PrP(C) and without alteration of its proteasomal or lysosomal degradation. Direct assessment of the protein synthesis rate and shotgun mass spectrometry proteomics analysis suggest that the reduction of PrP(C) is related to the impairment of global protein synthesis in CaN-KO astrocytes. When WT-PrP and PrP-D177N, a mouse homologue of a human mutation associated with the inherited prion disease fatal familial insomnia, were expressed in astrocytes, CaN-KO astrocytes showed an aberrant localization of both WT-PrP and PrP-D177N variants with predominant localization to the Golgi apparatus, suggesting that ablation of CaN affects both WT and mutant PrP proteins. These results provide new mechanistic details in relation to the regulation of PrP expression in astrocytes, suggesting the therapeutic potential of astroglial cells.
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Key words
astrocytes, calcineurin, FK506, prion protein, protein synthesis, calcium, neuroinflammation
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