Calcineurin Controls Cellular Prion Protein Expression in Mouse Astrocytes

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Prion diseases involve the misfolding of cellular prion protein (PrP^C) into infectious PrP^Sc.
• Astrocytes express PrP^C and can replicate PrP^Sc, making them relevant to prion disease pathogenesis.
• Reducing PrP^C is a promising therapeutic strategy for incurable prion diseases.

Purpose of the Study:

• To investigate the role of calcineurin (CaN) in regulating PrP^C expression in astrocytes.
• To determine the impact of CaN inhibition on PrP^C levels and localization in astrocytes, both in vitro and in vivo.
• To explore the therapeutic potential of targeting astroglial CaN for prion disease treatment.

Main Methods:

• Genetic ablation and pharmacological inhibition of CaN in astrocytes.
• Immunocytochemical analysis of cultured astrocytes and synaptosomal compartments from mice.
• Assessment of protein synthesis rates and proteomic analysis using mass spectrometry.
• Expression of wild-type and mutant PrP variants in astrocytes.

Main Results:

• Astrocyte-specific ablation or inhibition of CaN significantly reduces PrP^C expression.
• PrP^C downregulation occurs without changes in glycosylation or degradation pathways.
• Reduced PrP^C levels correlate with impaired global protein synthesis in CaN-deficient astrocytes.
• CaN deficiency leads to aberrant Golgi apparatus localization of both wild-type and mutant PrP.

Conclusions:

• Calcineurin in astrocytes plays a critical role in regulating PrP^C expression.
• Targeting astroglial CaN impacts PrP^C synthesis and localization, offering a novel therapeutic approach.
• Modulating CaN in astrocytes presents a potential strategy for managing prion diseases.