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Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease

BACKGROUND: Increasing evidence suggests that inflammation associated with microglial cell activation in the substantia nigra (SN) of patients with Parkinson disease (PD) is not only a consequence of neuronal degeneration, but may actively sustain dopaminergic (DA) cell loss over time. We aimed to s...

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Autores principales: Noelker, Carmen, Morel, Lydie, Osterloh, Anke, Alvarez-Fischer, Daniel, Lescot, Thomas, Breloer, Minka, Gold, Maike, Oertel, Wolfgang H, Henze, Carmen, Michel, Patrick P, Dodel, Richard C, Lu, Lixia, Hirsch, Etienne C, Hunot, Stéphane, Hartmann, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018945/
https://www.ncbi.nlm.nih.gov/pubmed/24886419
http://dx.doi.org/10.1186/1742-2094-11-86
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author Noelker, Carmen
Morel, Lydie
Osterloh, Anke
Alvarez-Fischer, Daniel
Lescot, Thomas
Breloer, Minka
Gold, Maike
Oertel, Wolfgang H
Henze, Carmen
Michel, Patrick P
Dodel, Richard C
Lu, Lixia
Hirsch, Etienne C
Hunot, Stéphane
Hartmann, Andreas
author_facet Noelker, Carmen
Morel, Lydie
Osterloh, Anke
Alvarez-Fischer, Daniel
Lescot, Thomas
Breloer, Minka
Gold, Maike
Oertel, Wolfgang H
Henze, Carmen
Michel, Patrick P
Dodel, Richard C
Lu, Lixia
Hirsch, Etienne C
Hunot, Stéphane
Hartmann, Andreas
author_sort Noelker, Carmen
collection PubMed
description BACKGROUND: Increasing evidence suggests that inflammation associated with microglial cell activation in the substantia nigra (SN) of patients with Parkinson disease (PD) is not only a consequence of neuronal degeneration, but may actively sustain dopaminergic (DA) cell loss over time. We aimed to study whether the intracellular chaperone heat shock protein 60 (Hsp60) could serve as a signal of CNS injury for activation of microglial cells. METHODS: Hsp60 mRNA expression in the mesencephalon and the striatum of C57/BL6 mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and the Hsp60/TH mRNA ratios in the SN of PD patients and aged-matched subjects were measured. To further investigate a possible link between the neuronal Hsp60 response and PD-related cellular stress, Hsp60 immunoblot analysis and quantification in cell lysates from SH-SY5Y after treatment with 100 μM MPP(+) (1-methyl-4-phenylpyridinium) at different time points (6, 12, 24 and 48 hours) compared to control cells were performed. Additional MTT and LDH assay were used. We next addressed the question as to whether Hsp60 influences the survival of TH(+) neurons in mesencephalic neuron-glia cultures treated either with MPP(+) (1 μM), hHsp60 (10 μg/ml) or a combination of both. Finally, we measured IL-1β, IL-6, TNF-α and NO-release by ELISA in primary microglial cell cultures following treatment with different hHsp60 preparations. Control cultures were exposed to LPS. RESULTS: In the mesencephalon and striatum of mice treated with MPTP and also in the SN of PD patients, we found that Hsp60 mRNA was up-regulated. MPP(+), the active metabolite of MPTP, also caused an increased expression and release of Hsp60 in the human dopaminergic cell line SH-SY5Y. Interestingly, in addition to being toxic to DA neurons in primary mesencephalic cultures, exogenous Hsp60 aggravated the effects of MPP(+). Yet, although we demonstrated that Hsp60 specifically binds to microglial cells, it failed to stimulate the production of pro-inflammatory cytokines or NO by these cells. CONCLUSIONS: Overall, our data suggest that Hsp60 is likely to participate in DA cell death in PD but via a mechanism unrelated to cytokine release.
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spelling pubmed-40189452014-05-14 Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease Noelker, Carmen Morel, Lydie Osterloh, Anke Alvarez-Fischer, Daniel Lescot, Thomas Breloer, Minka Gold, Maike Oertel, Wolfgang H Henze, Carmen Michel, Patrick P Dodel, Richard C Lu, Lixia Hirsch, Etienne C Hunot, Stéphane Hartmann, Andreas J Neuroinflammation Research BACKGROUND: Increasing evidence suggests that inflammation associated with microglial cell activation in the substantia nigra (SN) of patients with Parkinson disease (PD) is not only a consequence of neuronal degeneration, but may actively sustain dopaminergic (DA) cell loss over time. We aimed to study whether the intracellular chaperone heat shock protein 60 (Hsp60) could serve as a signal of CNS injury for activation of microglial cells. METHODS: Hsp60 mRNA expression in the mesencephalon and the striatum of C57/BL6 mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and the Hsp60/TH mRNA ratios in the SN of PD patients and aged-matched subjects were measured. To further investigate a possible link between the neuronal Hsp60 response and PD-related cellular stress, Hsp60 immunoblot analysis and quantification in cell lysates from SH-SY5Y after treatment with 100 μM MPP(+) (1-methyl-4-phenylpyridinium) at different time points (6, 12, 24 and 48 hours) compared to control cells were performed. Additional MTT and LDH assay were used. We next addressed the question as to whether Hsp60 influences the survival of TH(+) neurons in mesencephalic neuron-glia cultures treated either with MPP(+) (1 μM), hHsp60 (10 μg/ml) or a combination of both. Finally, we measured IL-1β, IL-6, TNF-α and NO-release by ELISA in primary microglial cell cultures following treatment with different hHsp60 preparations. Control cultures were exposed to LPS. RESULTS: In the mesencephalon and striatum of mice treated with MPTP and also in the SN of PD patients, we found that Hsp60 mRNA was up-regulated. MPP(+), the active metabolite of MPTP, also caused an increased expression and release of Hsp60 in the human dopaminergic cell line SH-SY5Y. Interestingly, in addition to being toxic to DA neurons in primary mesencephalic cultures, exogenous Hsp60 aggravated the effects of MPP(+). Yet, although we demonstrated that Hsp60 specifically binds to microglial cells, it failed to stimulate the production of pro-inflammatory cytokines or NO by these cells. CONCLUSIONS: Overall, our data suggest that Hsp60 is likely to participate in DA cell death in PD but via a mechanism unrelated to cytokine release. BioMed Central 2014-05-08 /pmc/articles/PMC4018945/ /pubmed/24886419 http://dx.doi.org/10.1186/1742-2094-11-86 Text en Copyright © 2014 Noelker et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
Noelker, Carmen
Morel, Lydie
Osterloh, Anke
Alvarez-Fischer, Daniel
Lescot, Thomas
Breloer, Minka
Gold, Maike
Oertel, Wolfgang H
Henze, Carmen
Michel, Patrick P
Dodel, Richard C
Lu, Lixia
Hirsch, Etienne C
Hunot, Stéphane
Hartmann, Andreas
Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease
title Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease
title_full Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease
title_fullStr Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease
title_full_unstemmed Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease
title_short Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease
title_sort heat shock protein 60: an endogenous inducer of dopaminergic cell death in parkinson disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018945/
https://www.ncbi.nlm.nih.gov/pubmed/24886419
http://dx.doi.org/10.1186/1742-2094-11-86
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