Ubiquitin-proteasome system impairment and MPTP-induced oxidative stress in the brain of C57BL/6 wild-type and GSTP knockout mice

Andreia Neves Carvalho, Carla Marques, Elsa Rodrigues, Colin J Henderson, C Roland Wolf, Paulo Pereira, Maria João Gama

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    The ubiquitin-proteasome system (UPS) is the primary proteolytic complex responsible for the elimination of damaged and misfolded intracellular proteins, often formed upon oxidative stress. Parkinson's disease (PD) is neuropathologically characterized by selective death of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracytoplasmic inclusions of aggregated proteins. Along with mitochondrial dysfunction and oxidative stress, defects in the UPS have been implicated in PD. Glutathione S-transferase pi (GSTP) is a phase II detoxifying enzyme displaying important defensive roles against the accumulation of reactive metabolites that potentiate the aggression of SN neuronal cells, by regulating several processes including S-glutathionylation, modulation of glutathione levels and control of kinase-catalytic activities. In this work we used C57BL/6 wild-type and GSTP knockout mice to elucidate the effect of both MPTP and MG132 in the UPS function and to clarify if the absence of GSTP alters the response of this pathway to the neurotoxin and proteasome inhibitor insults. Our results demonstrate that different components of the UPS have different susceptibilities to oxidative stress. Importantly, when compared to the wild-type, GSTP knockout mice display decreased ubiquitination capacity and overall increased susceptibility to UPS damage and inactivation upon MPTP-induced oxidative stress.
    Original languageEnglish
    Pages (from-to)662-72
    Number of pages11
    JournalMolecular Neurobiology
    Volume47
    Issue number2
    DOIs
    Publication statusPublished - Apr 2013

    Fingerprint

    Glutathione S-Transferase pi
    1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    Proteasome Endopeptidase Complex
    Ubiquitin
    Knockout Mice
    Oxidative Stress
    Brain
    Substantia Nigra
    Parkinson Disease
    Proteasome Inhibitors
    Ubiquitination
    Dopaminergic Neurons
    Neurotoxins
    Aggression
    Glutathione
    Proteins
    Phosphotransferases
    Enzymes

    Cite this

    Carvalho, Andreia Neves ; Marques, Carla ; Rodrigues, Elsa ; Henderson, Colin J ; Wolf, C Roland ; Pereira, Paulo ; Gama, Maria João. / Ubiquitin-proteasome system impairment and MPTP-induced oxidative stress in the brain of C57BL/6 wild-type and GSTP knockout mice. In: Molecular Neurobiology. 2013 ; Vol. 47, No. 2. pp. 662-72.
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    abstract = "The ubiquitin-proteasome system (UPS) is the primary proteolytic complex responsible for the elimination of damaged and misfolded intracellular proteins, often formed upon oxidative stress. Parkinson's disease (PD) is neuropathologically characterized by selective death of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracytoplasmic inclusions of aggregated proteins. Along with mitochondrial dysfunction and oxidative stress, defects in the UPS have been implicated in PD. Glutathione S-transferase pi (GSTP) is a phase II detoxifying enzyme displaying important defensive roles against the accumulation of reactive metabolites that potentiate the aggression of SN neuronal cells, by regulating several processes including S-glutathionylation, modulation of glutathione levels and control of kinase-catalytic activities. In this work we used C57BL/6 wild-type and GSTP knockout mice to elucidate the effect of both MPTP and MG132 in the UPS function and to clarify if the absence of GSTP alters the response of this pathway to the neurotoxin and proteasome inhibitor insults. Our results demonstrate that different components of the UPS have different susceptibilities to oxidative stress. Importantly, when compared to the wild-type, GSTP knockout mice display decreased ubiquitination capacity and overall increased susceptibility to UPS damage and inactivation upon MPTP-induced oxidative stress.",
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    Ubiquitin-proteasome system impairment and MPTP-induced oxidative stress in the brain of C57BL/6 wild-type and GSTP knockout mice. / Carvalho, Andreia Neves; Marques, Carla; Rodrigues, Elsa; Henderson, Colin J; Wolf, C Roland; Pereira, Paulo; Gama, Maria João.

    In: Molecular Neurobiology, Vol. 47, No. 2, 04.2013, p. 662-72.

    Research output: Contribution to journalArticle

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