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Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation

BACKGROUND: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiology of...

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Autores principales: Pinto, Milena, Nissanka, Nadee, Peralta, Susana, Brambilla, Roberta, Diaz, Francisca, Moraes, Carlos T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818913/
https://www.ncbi.nlm.nih.gov/pubmed/27038906
http://dx.doi.org/10.1186/s13024-016-0090-7
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author Pinto, Milena
Nissanka, Nadee
Peralta, Susana
Brambilla, Roberta
Diaz, Francisca
Moraes, Carlos T.
author_facet Pinto, Milena
Nissanka, Nadee
Peralta, Susana
Brambilla, Roberta
Diaz, Francisca
Moraes, Carlos T.
author_sort Pinto, Milena
collection PubMed
description BACKGROUND: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiology of PD is unknown, mitochondrial dysfunctions, including cytochrome c oxidase (Complex IV) impairment in dopaminergic neurons, have been associated with the disease’s pathophysiology. In order to analyze the role of Complex IV in PD, we knocked out Cox10 (essential for the maturation of COXI, a catalytic subunit of Complex IV) in dopaminergic neurons. We also tested whether the resulting phenotype was improved by stimulating the PPAR-γ pathway. RESULTS: Cox10/DAT-cre mice showed decreased numbers of TH+ and DAT+ cells in the substantia nigra, early striatal dopamine depletion, motor defects reversible with L-DOPA treatment and hypersensitivity to L-DOPA with hyperkinetic behavior. We found that chronic pioglitazone (PPAR-γ agonist) treatment ameliorated the motor phenotype in Cox10/DAT-cre mice. Although neither mitochondrial function nor the number of dopaminergic neurons was improved, neuroinflammation in the midbrain and the striatum was decreased. CONCLUSIONS: By triggering a mitochondrial Complex IV defect in dopaminergic neurons, we created a new mouse model resembling the late stages of PD with massive degeneration of dopaminergic neurons and striatal dopamine depletion. The motor phenotypes were improved by Pioglitazone treatment, suggesting that targetable secondary pathways can influence the development of certain forms of PD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0090-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-48189132016-04-04 Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation Pinto, Milena Nissanka, Nadee Peralta, Susana Brambilla, Roberta Diaz, Francisca Moraes, Carlos T. Mol Neurodegener Research Article BACKGROUND: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiology of PD is unknown, mitochondrial dysfunctions, including cytochrome c oxidase (Complex IV) impairment in dopaminergic neurons, have been associated with the disease’s pathophysiology. In order to analyze the role of Complex IV in PD, we knocked out Cox10 (essential for the maturation of COXI, a catalytic subunit of Complex IV) in dopaminergic neurons. We also tested whether the resulting phenotype was improved by stimulating the PPAR-γ pathway. RESULTS: Cox10/DAT-cre mice showed decreased numbers of TH+ and DAT+ cells in the substantia nigra, early striatal dopamine depletion, motor defects reversible with L-DOPA treatment and hypersensitivity to L-DOPA with hyperkinetic behavior. We found that chronic pioglitazone (PPAR-γ agonist) treatment ameliorated the motor phenotype in Cox10/DAT-cre mice. Although neither mitochondrial function nor the number of dopaminergic neurons was improved, neuroinflammation in the midbrain and the striatum was decreased. CONCLUSIONS: By triggering a mitochondrial Complex IV defect in dopaminergic neurons, we created a new mouse model resembling the late stages of PD with massive degeneration of dopaminergic neurons and striatal dopamine depletion. The motor phenotypes were improved by Pioglitazone treatment, suggesting that targetable secondary pathways can influence the development of certain forms of PD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0090-7) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-02 /pmc/articles/PMC4818913/ /pubmed/27038906 http://dx.doi.org/10.1186/s13024-016-0090-7 Text en © Pinto et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.
spellingShingle Research Article
Pinto, Milena
Nissanka, Nadee
Peralta, Susana
Brambilla, Roberta
Diaz, Francisca
Moraes, Carlos T.
Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation
title Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation
title_full Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation
title_fullStr Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation
title_full_unstemmed Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation
title_short Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation
title_sort pioglitazone ameliorates the phenotype of a novel parkinson’s disease mouse model by reducing neuroinflammation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818913/
https://www.ncbi.nlm.nih.gov/pubmed/27038906
http://dx.doi.org/10.1186/s13024-016-0090-7
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