title: Ubiquitin-proteasome system impairment and MPTP-induced oxidative stress in the brain of C57BL/6 wild-type and GSTP knockout mice.
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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMED.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Andreia Neves
authors.initials: AN
authors.lastname: Carvalho
authors.forename: Carla
authors.initials: C
authors.lastname: Marques
authors.forename: Elsa
authors.initials: E
authors.lastname: Rodrigues
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.forename: Paulo
authors.initials: P
authors.lastname: Pereira
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Gama
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D058767:Protein Unfolding / Q000187:drug effects; D025801:Ubiquitin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051549:Glutathione S-Transferase pi; D046988:Proteasome Endopeptidase Complex