Cyclophillin A deficiency accelerates RML-induced prion disease

Area of Science:

• Neuroscience
• Immunology
• Protein Biochemistry

Background:

• Prion diseases involve abnormal prion protein aggregation in the brain, triggering glial activation and cytokine release.
• Cyclophilin A (CypA), a protein isomerase, is secreted during inflammation and was previously proposed to mediate glial activation in vitro.
• The in vivo role of CypA in prion disease pathogenesis remained unclear.

Purpose of the Study:

• To investigate the in vivo role of Cyclophilin A (CypA) in prion disease progression and glial response.
• To determine if CypA influences the onset of neurological signs, survival rates, and glial activation (microglia and astrocytes) during prion infection.

Main Methods:

• Inoculation of CypA-expressing (CypA+/+), heterozygous (CypA+/-), and deficient (CypA-/-) mice with the RML prion strain.
• Monitoring of neurological symptom onset, disease progression, and survival times.
• Analysis of astrocyte and microglia activation and inflammatory markers at presymptomatic and symptomatic stages.

Main Results:

• CypA-deficient mice exhibited significantly shorter survival times and earlier onset of neurological signs compared to controls.
• Presymptomatic CypA-deficient mice showed markedly increased microglial activation.
• Analysis revealed a shift towards a pro-inflammatory microglial phenotype in CypA-deficient mice, while astrocyte activation remained unchanged.

Conclusions:

• CypA plays a role in modulating the host's response to prion infection in vivo.
• CypA appears to dampen the pro-inflammatory microglial response during the early, presymptomatic stages of RML prion disease.
• These findings suggest CypA as a potential therapeutic target for mitigating neuroinflammation in prion diseases.