Cargando…

3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Pa...

Descripción completa

Detalles Bibliográficos
Autores principales: Luxenburger, Andreas, Clemmens, Hannah, Hastings, Christopher, Harris, Lawrence D., Ure, Elizabeth M., Cameron, Scott A., Aasly, Jan, Bandmann, Oliver, Weymouth-Wilson, Alex, Furneaux, Richard H., Mortiboys, Heather
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855844/
https://www.ncbi.nlm.nih.gov/pubmed/36671460
http://dx.doi.org/10.3390/biom13010076
_version_ 1784873475263954944
author Luxenburger, Andreas
Clemmens, Hannah
Hastings, Christopher
Harris, Lawrence D.
Ure, Elizabeth M.
Cameron, Scott A.
Aasly, Jan
Bandmann, Oliver
Weymouth-Wilson, Alex
Furneaux, Richard H.
Mortiboys, Heather
author_facet Luxenburger, Andreas
Clemmens, Hannah
Hastings, Christopher
Harris, Lawrence D.
Ure, Elizabeth M.
Cameron, Scott A.
Aasly, Jan
Bandmann, Oliver
Weymouth-Wilson, Alex
Furneaux, Richard H.
Mortiboys, Heather
author_sort Luxenburger, Andreas
collection PubMed
description Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease.
format Online
Article
Text
id pubmed-9855844
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-98558442023-01-21 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease Luxenburger, Andreas Clemmens, Hannah Hastings, Christopher Harris, Lawrence D. Ure, Elizabeth M. Cameron, Scott A. Aasly, Jan Bandmann, Oliver Weymouth-Wilson, Alex Furneaux, Richard H. Mortiboys, Heather Biomolecules Article Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease. MDPI 2022-12-30 /pmc/articles/PMC9855844/ /pubmed/36671460 http://dx.doi.org/10.3390/biom13010076 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Luxenburger, Andreas
Clemmens, Hannah
Hastings, Christopher
Harris, Lawrence D.
Ure, Elizabeth M.
Cameron, Scott A.
Aasly, Jan
Bandmann, Oliver
Weymouth-Wilson, Alex
Furneaux, Richard H.
Mortiboys, Heather
3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease
title 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease
title_full 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease
title_fullStr 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease
title_full_unstemmed 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease
title_short 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease
title_sort 3α,7-dihydroxy-14(13→12)abeo-5β,12α(h),13β(h)-cholan-24-oic acids display neuroprotective properties in common forms of parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855844/
https://www.ncbi.nlm.nih.gov/pubmed/36671460
http://dx.doi.org/10.3390/biom13010076
work_keys_str_mv AT luxenburgerandreas 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT clemmenshannah 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT hastingschristopher 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT harrislawrenced 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT ureelizabethm 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT cameronscotta 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT aaslyjan 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT bandmannoliver 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT weymouthwilsonalex 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT furneauxrichardh 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease
AT mortiboysheather 3a7dihydroxy141312abeo5b12ah13bhcholan24oicacidsdisplayneuroprotectivepropertiesincommonformsofparkinsonsdisease