Detrimental effects of oxidative losses in parkin activity in a model of sporadic Parkinson's disease are attenuated by restoration of PGC1alpha.
Neurobiol Dis
; 93: 115-20, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27185595
ABSTRACT
Loss of parkin E3 ligase activity as a result of parkin gene mutation in rare familial forms of Parkinson's disease (PD) has been shown to be detrimental to mitochondrial function and to contribute to ensuing neurodegeneration. This has been shown by ourselves and others to be in part due to reductions in parkin-mediated ubiquitination of the transcriptional repressor PARIS, limiting the protein's subsequent degradation by the proteasome. Subsequent elevations in PARIS protein levels result in reduced expression of the master mitochondrial regulator PGC-1α, impacting in turn on mitochondrial function. Here, we report that oxidatively-mediated reductions in parkin solubility and function in a mouse model of age-related sporadic PD coincides with increased PARIS levels and reduced PGC-1α signaling. Furthermore, restoration of PGC-1α expression was found to abrogate losses in mitochondrial function and degeneration of dopaminergic (DAergic) neurons within the substantia nigra pars compacta (SNpc) associated with this particular model. These findings suggest that the PGC-1α signaling pathway constitutes a viable therapeutic target for the treatment of not only familial PD, but also more common sporadic forms of the disorder.
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MEDLINE
Assunto principal:
Doença de Parkinson
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Estresse Oxidativo
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Ubiquitina-Proteína Ligases
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Neurônios Dopaminérgicos
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Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article