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NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease

BACKGROUND: Without appropriate cellular models the etiology of idiopathic Parkinson's disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functiona...

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Autores principales: Cook, Anthony L., Vitale, Alejandra M., Ravishankar, Sugandha, Matigian, Nicholas, Sutherland, Greg T., Shan, Jiangou, Sutharsan, Ratneswary, Perry, Chris, Silburn, Peter A., Mellick, George D., Whitelaw, Murray L., Wells, Christine A., Mackay-Sim, Alan, Wood, Stephen A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128624/
https://www.ncbi.nlm.nih.gov/pubmed/21747966
http://dx.doi.org/10.1371/journal.pone.0021907
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author Cook, Anthony L.
Vitale, Alejandra M.
Ravishankar, Sugandha
Matigian, Nicholas
Sutherland, Greg T.
Shan, Jiangou
Sutharsan, Ratneswary
Perry, Chris
Silburn, Peter A.
Mellick, George D.
Whitelaw, Murray L.
Wells, Christine A.
Mackay-Sim, Alan
Wood, Stephen A.
author_facet Cook, Anthony L.
Vitale, Alejandra M.
Ravishankar, Sugandha
Matigian, Nicholas
Sutherland, Greg T.
Shan, Jiangou
Sutharsan, Ratneswary
Perry, Chris
Silburn, Peter A.
Mellick, George D.
Whitelaw, Murray L.
Wells, Christine A.
Mackay-Sim, Alan
Wood, Stephen A.
author_sort Cook, Anthony L.
collection PubMed
description BACKGROUND: Without appropriate cellular models the etiology of idiopathic Parkinson's disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson's disease. RESULTS: We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H(2)O(2) than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson's Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson's disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. CONCLUSIONS: Our results confirmed NRF2 as a potential therapeutic target for Parkinson's disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics.
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spelling pubmed-31286242011-07-11 NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease Cook, Anthony L. Vitale, Alejandra M. Ravishankar, Sugandha Matigian, Nicholas Sutherland, Greg T. Shan, Jiangou Sutharsan, Ratneswary Perry, Chris Silburn, Peter A. Mellick, George D. Whitelaw, Murray L. Wells, Christine A. Mackay-Sim, Alan Wood, Stephen A. PLoS One Research Article BACKGROUND: Without appropriate cellular models the etiology of idiopathic Parkinson's disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson's disease. RESULTS: We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H(2)O(2) than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson's Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson's disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. CONCLUSIONS: Our results confirmed NRF2 as a potential therapeutic target for Parkinson's disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics. Public Library of Science 2011-07-01 /pmc/articles/PMC3128624/ /pubmed/21747966 http://dx.doi.org/10.1371/journal.pone.0021907 Text en Cook et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cook, Anthony L.
Vitale, Alejandra M.
Ravishankar, Sugandha
Matigian, Nicholas
Sutherland, Greg T.
Shan, Jiangou
Sutharsan, Ratneswary
Perry, Chris
Silburn, Peter A.
Mellick, George D.
Whitelaw, Murray L.
Wells, Christine A.
Mackay-Sim, Alan
Wood, Stephen A.
NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease
title NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease
title_full NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease
title_fullStr NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease
title_full_unstemmed NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease
title_short NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease
title_sort nrf2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic parkinson's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128624/
https://www.ncbi.nlm.nih.gov/pubmed/21747966
http://dx.doi.org/10.1371/journal.pone.0021907
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