title: Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons.
abstract: Alpha-synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease. The native protein is a major component of nigral Lewy bodies in Parkinson's disease, and full-length alpha-synuclein accumulates in Lewy neurites. Here we present evidence that alpha-synuclein levels are elevated in midbrain dopamine (DA) neurons of chronic cocaine abusers. Western blot and immunoautoradiographic studies were conducted on postmortem neuropathological specimens from cocaine users and age-matched drug-free control subjects. The results demonstrated that alpha-synuclein levels in the DA cell groups of the substantia nigra/ventral tegmental complex were elevated threefold in chronic cocaine users compared with normal age-matched subjects. The increased protein levels in chronic cocaine users were accompanied by changes in the expression of alpha-synuclein mRNA in the substantia nigra and ventral tegmental area. Although alpha-synuclein expression is prominent in the hippocampus, there was no increase in protein expression in this brain region. The levels of beta-synuclein, a possible negative regulator of alpha-synuclein, also were not affected by cocaine exposure. Alpha-synuclein protein levels were increased in the ventral tegmental area, but not the substantia nigra, in victims of excited cocaine delirium who experienced paranoia, marked agitation, and hyperthermia before death. The overexpression of alpha-synuclein may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse. However, the accumulation of alpha-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.
authors.affiliation: Department of Neurology, University of Miami School of Medicine, Miami, Florida 33101, USA. dmash@newssun.med.miami.edu
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Ouyang
authors.forename: John
authors.initials: J
authors.lastname: Pablo
authors.forename: Margaret
authors.initials: M
authors.lastname: Basile
authors.forename: Sari
authors.initials: S
authors.lastname: Izenwasser
authors.forename: Abraham
authors.initials: A
authors.lastname: Lieberman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perrin
mesh_terms: D015153:Blotting, Western; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis*; D005786:Gene Expression Regulation; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051843:Synucleins; D014158:Transcription, Genetic; D051844:alpha-Synuclein; D051846:beta-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D004298:Dopamine