Abstract
Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. 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 major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. 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 cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.
Highlights
Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of devastating, infectious and fatal neurodegenerative disorders caused by proteinaceous infectious pathogens termed as prions
Cyp46A1 signals were quantified, and the results indicate a significant reduction of Cyp46A1 in brain homogenates at the terminal stage of prion disease (RML, 22L, and ME7; p < 0.01) compared to the age-matched noninfected mice (Fig. 1c; p < 0.01)
To the best of our knowledge, our study provides the first evidence of significantly decreased levels of Cyp46A1 in prion-infected neuronal cells, in brains of mice infected with different prion strains at the terminal disease stage and most importantly, in post-mortem brains of sporadic Creutzfeldt-Jakob disease (sCJD) patients
Summary
Transmissible spongiform encephalopathies (TSEs), are a group of devastating, infectious and fatal neurodegenerative disorders caused by proteinaceous infectious pathogens termed as prions. Prion diseases affect both humans and animals. Animal prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in cervids (elk, mule deer, whitetailed deer, moose and reindeer) [1,2,3,4,5]. The possibility of zoonotic transmission as demonstrated by BSE and the resulting vCJD, and the unknown potential of CWD to cross the species barrier to humans impose a challenge especially in the absence of therapeutics. It is of paramount importance to identify new drug
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
