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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

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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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Acknowledgments

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) and FEDER through grants PPCDT/SAU-FCF/58171/2004, PTDC/SAU-MMO/57216/2004 and PEst-OE/SAU/UI4013/2011, and PhD fellowship SFRH/BD/39897/2007 (to ANC).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Research Institute for Medicines and Pharmaceutical Sciences (iMED.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Andreia Neves Carvalho, Elsa Rodrigues & Maria João Gama

  2. Centre of Ophthalmology and Vision Science, Institute of Biomedical Research in Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta. Comba, Celas 3000-548, Coimbra, Portugal

    Andreia Neves Carvalho, Carla Marques & Paulo Pereira

  3. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Elsa Rodrigues & Maria João Gama

  4. Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland, UK

    Colin J. Henderson & C. Roland Wolf

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  1. Andreia Neves Carvalho
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  2. Carla Marques
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  3. Elsa Rodrigues
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  4. Colin J. Henderson
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  6. Paulo Pereira
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  7. Maria João Gama
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Correspondence to Maria João Gama.

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A. N. Carvalho and C. Marques are joint first authors.

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Carvalho, A.N., Marques, C., Rodrigues, E. et al. Ubiquitin–Proteasome System Impairment and MPTP-Induced Oxidative Stress in the Brain of C57BL/6 Wild-type and GSTP Knockout Mice. Mol Neurobiol 47, 662–672 (2013). https://doi.org/10.1007/s12035-012-8368-4

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