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Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice
Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrP(C)) into the infectious isoform (PrP(Sc)). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being th...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017635/ https://www.ncbi.nlm.nih.gov/pubmed/33795005 http://dx.doi.org/10.1186/s40478-021-01162-1 |
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author | Ali, Tahir Hannaoui, Samia Nemani, Satish Tahir, Waqas Zemlyankina, Irina Cherry, Pearl Shim, Su Yeon Sim, Valerie Schaetzl, Hermann M. Gilch, Sabine |
author_facet | Ali, Tahir Hannaoui, Samia Nemani, Satish Tahir, Waqas Zemlyankina, Irina Cherry, Pearl Shim, Su Yeon Sim, Valerie Schaetzl, Hermann M. Gilch, Sabine |
author_sort | Ali, Tahir |
collection | PubMed |
description | Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrP(C)) into the infectious isoform (PrP(Sc)). 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 PrP(Sc) propagation in prion-infected cells while preserving physiological PrP(C) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01162-1. |
format | Online Article Text |
id | pubmed-8017635 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-80176352021-04-02 Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice Ali, Tahir Hannaoui, Samia Nemani, Satish Tahir, Waqas Zemlyankina, Irina Cherry, Pearl Shim, Su Yeon Sim, Valerie Schaetzl, Hermann M. Gilch, Sabine Acta Neuropathol Commun Research Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrP(C)) into the infectious isoform (PrP(Sc)). 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 PrP(Sc) propagation in prion-infected cells while preserving physiological PrP(C) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01162-1. BioMed Central 2021-04-01 /pmc/articles/PMC8017635/ /pubmed/33795005 http://dx.doi.org/10.1186/s40478-021-01162-1 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Ali, Tahir Hannaoui, Samia Nemani, Satish Tahir, Waqas Zemlyankina, Irina Cherry, Pearl Shim, Su Yeon Sim, Valerie Schaetzl, Hermann M. Gilch, Sabine Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice |
title | Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice |
title_full | Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice |
title_fullStr | Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice |
title_full_unstemmed | Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice |
title_short | Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice |
title_sort | oral administration of repurposed drug targeting cyp46a1 increases survival times of prion infected mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017635/ https://www.ncbi.nlm.nih.gov/pubmed/33795005 http://dx.doi.org/10.1186/s40478-021-01162-1 |
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