Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo

Anna Moszczynska, Bryan K. Yamamoto

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1005-1017
Number of pages13
JournalJournal of Neurochemistry
Volume116
Issue number6
DOIs
StatePublished - Mar 1 2011

Fingerprint

Methamphetamine
Proteasome Endopeptidase Complex
Corpus Striatum
Ubiquitin
Poisons
Lipids
Proteins
Oxidative stress
Synaptosomes
Chymotrypsin
Metabolites
ATP dependent 26S protease
Vitamin E
Lipid Peroxidation
Toxicity
Rats
Animals
Oxidative Stress
Tissue
Injections

Keywords

  • 4-hydroxy-2-nonenal
  • dopamine
  • methamphetamine
  • parkin
  • proteasome
  • toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo. / Moszczynska, Anna; Yamamoto, Bryan K.

In: Journal of Neurochemistry, Vol. 116, No. 6, 01.03.2011, p. 1005-1017.

Research output: Contribution to journalArticle

@article{280ea5d48a0640f2b3d4363a6a14fa2c,
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.",
keywords = "4-hydroxy-2-nonenal, dopamine, methamphetamine, parkin, proteasome, toxicity",
author = "Anna Moszczynska and Yamamoto, {Bryan K.}",
year = "2011",
month = "3",
day = "1",
doi = "10.1111/j.1471-4159.2010.07147.x",
language = "English (US)",
volume = "116",
pages = "1005--1017",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo

AU - Moszczynska, Anna

AU - Yamamoto, Bryan K.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - 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.

AB - 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.

KW - 4-hydroxy-2-nonenal

KW - dopamine

KW - methamphetamine

KW - parkin

KW - proteasome

KW - toxicity

UR - http://www.scopus.com/inward/record.url?scp=79952453410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952453410&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2010.07147.x

DO - 10.1111/j.1471-4159.2010.07147.x

M3 - Article

C2 - 21166679

AN - SCOPUS:79952453410

VL - 116

SP - 1005

EP - 1017

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 6

ER -