title: Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo.
abstract: Methamphetamine (METH) is toxic to dopaminergic (DAergic) terminals in animals and humans. An early event in METH neurotoxicity is an oxidative stress followed by damage to proteins and lipids. The removal of damaged proteins is accomplished by the ubiquitin-proteasome system (UPS) and the impairment of this system can cause neurodegeneration. Whether dysfunction of the UPS contributes to METH toxicity to DAergic terminals has not been determined. The present investigation examined the effects of METH on functions of parkin and proteasome in rat striatal synaptosomes. METH rapidly modified parkin via conjugation with 4-hydroxy-2-nonenal (4-HNE) to decrease parkin levels and decreased the activity of the 26S proteasome while simultaneously increasing chymotrypsin-like activity and 20S proteasome levels. Prior injections of vitamin E diminished METH-induced changes to parkin and the 26S proteasome as well as long-term decreases in DA and its metabolites' concentrations in striatal tissue. These results suggest that METH causes lipid peroxidation-mediated damage to parkin and the 26S proteasome. As the changes in parkin and 26S occur before the sustained deficits in DAergic markers, an early loss of UPS function may be important in mediating the long-term degeneration of striatal DAergic terminals via toxic accumulation of parkin substrates and damaged proteins.
authors.affiliation: Department of Neurosciences, University of Toledo College of Medicine, Toledo, Ohio, USA. amosz@wayne.edu
authors.forename: Anna
authors.initials: A
authors.lastname: Moszczynska
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Yamamoto
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D003342:Corpus Striatum / Q000648:ultrastructure; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026403:S-Nitrosothiols / Q000378:metabolism; D018709:Statistics, Nonparametric; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D018765:Dopamine Uptake Inhibitors; D026403:S-Nitrosothiols; D014404:Tubulin; D014810:Vitamin E; D008694:Methamphetamine; C021315:S-nitrosocysteine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C027576:4-hydroxy-2-nonenal; D003545:Cysteine; D004298:Dopamine