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Methamphetamine oxidatively modifies the E3 ligase parkin and attenuates the activity of 26S proteasome in vivo
Author(s) -
Moszczynska Anna,
Yamamoto Bryan K
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.759.3
Subject(s) - parkin , meth , ubiquitin ligase , neurotoxicity , oxidative stress , proteasome , chemistry , ubiquitin , pharmacology , in vivo , lipid peroxidation , antioxidant , glutathione , biochemistry , biology , toxicity , enzyme , parkinson's disease , medicine , genetics , disease , monomer , organic chemistry , acrylate , gene , polymer
One of the mechanisms involved in METH neurotoxicity is oxidative stress. Oxidatively damaged proteins are degraded by the ubiquitin proteasome system (UPS) which consists of the 26S proteasome and enzymes such as the E3 ligases. Disruption of the UPS promotes toxic accumulation of proteins. The objective of the present study was to examine the effect of METH on the E3 ligase parkin and proteasome in vivo . To address the hypothesis that METH decreases parkin function through oxidative stress and impairs function of the 26S proteasome, the levels of parkin, 4‐hydroxynonenal‐ and nitrosocysteine‐parkin conjugates as well as activity of 20S and 26S proteasome were examined in synaptosomes from male Sprague Dawley rats killed 1 h after the last injection of METH (4 × 10 mg/kg, 2 h apart, i.p.) or saline. METH caused a 41% decrease in parkin levels, a 28% increase in 4‐HNE‐modified parkin and a 51% decrease in 26S activity in striatal synaptosomes as compared to saline controls. Pretreatment of rats with vitamin E significantly diminished the METH‐induced changes. These results suggest that (1) there is lipid peroxidation‐mediated oxidative damage to parkin that leads to its subsequent degradation within 1 h after last dose of toxic METH and (2) decreases in parkin and 26S proteasome function might contribute to METH neurotoxicity via accumulation of oxidatively damaged proteins. Supported by NIH grants DA023085 and DA07606