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BRAIN-SPECIFIC CHOLESTEROL METABOLIZING ENZYME (CYP46A1) AS A NOVEL THERAPEUTIC TARGET IN HUMAN PRION DISEASES
Abstract
Aims
Prion diseases are a group of fatal and infectious neurodegenerative disorders. They affect both humans and animals. Creutzfeldt-Jakob disease (CJD) is the most common human prion disease. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The brain-specific enzyme, cholesterol 24-hydroxylase (CYP46A1) converts cholesterol into 24(S)-hydroxycholesterol that exits the brain. We aimed to determine the role of Cyp46A1 in prion disease and to verify pharmacological Cyp464A1 activation as a novel therapeutic approach.
Methods
Immunoblotting and confocal microscopy were performed on brains of prion-mice infected and in post-mortem brains of sporadic (sCJD) patients as well as in prion infected-neuronal/astrocyte cells and primary cerebellar granular neurons.
Results
We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal/astrocyte cells, and in post-mortem brains of sCJD patients. We have used the Cyp46A1 activator efavirenz (EFV) for the treatment of prion-infected neuronal cell lines, primary neurons, and mice. EFV is an FDA-approved anti-HIV medication crossing the blood-brain barrier. EFV treatment significantly mitigated the infectious prion protein isoform (PrPSc) in prion-infected cells and prevented de novo infection of primary neurons. Notably, oral administration of EFV at low dosage significantly prolonged the lifespan of prion-infected mice.
Conclusions
Our results suggest that Cyp46A1 as a novel therapeutic target and that its activation might be a valuable treatment approach for prion diseases.