title: Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system.
abstract: Sporadic Parkinson's disease (PD) is most likely caused by a combination of environmental exposures and genetic susceptibilities, although there are rare monogenic forms of the disease. Mitochondrial impairment at complex I, oxidative stress, alpha-synuclein aggregation, and dysfunctional protein degradation, have been implicated in PD pathogenesis, but how they are related to each other is unclear. To further evaluated PD pathogenesis here, we used in vivo and in vitro models of chronic low-grade complex I inhibition with the pesticide rotenone. Chronic rotenone exposure in vivo caused oxidative modification of DJ-1, accumulation of alpha-synuclein, and proteasomal impairment. Interestingly, the effects become more regionally restricted such that systemic complex I inhibition eventually results in highly selective degeneration of the nigrostriatal pathway. DJ-1 modifications, alpha-synuclein accumulation, and proteasomal dysfunction were also seen in vitro and these effects could be prevented with alpha-tocopherol. Thus, chronic exposure to a pesticide and mitochondrial toxin brings into play three systems, DJ-1, alpha-synuclein, and the ubiquitin-proteasome system, and implies that mitochondrial dysfunction and oxidative stress link environmental and genetic forms of the disease.
authors.affiliation: Center for Neurodegenerative Disease, Center for Neurodegenerative diseases, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA. rbetarb@emory.edu
authors.forename: Ranjita
authors.initials: R
authors.lastname: Betarbet
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Canet-Aviles
authors.forename: Todd B
authors.initials: TB
authors.lastname: Sherer
authors.forename: Pier G
authors.initials: PG
authors.lastname: Mastroberardino
authors.forename: Chris
authors.initials: C
authors.lastname: McLendon
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Serena
authors.initials: S
authors.lastname: Lund
authors.forename: Hye-Mee
authors.initials: HM
authors.lastname: Na
authors.forename: Georgia
authors.initials: G
authors.lastname: Taylor
authors.forename: Neil F
authors.initials: NF
authors.lastname: Bence
authors.forename: Ron
authors.initials: R
authors.lastname: Kopito
authors.forename: Byoung Boo
authors.initials: BB
authors.lastname: Seo
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
authors.forename: Akemi
authors.initials: A
authors.lastname: Yagi
authors.forename: Gary
authors.initials: G
authors.lastname: Klinefelter
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Greenamyre
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007306:Insecticides / Q000633:toxicity; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015513:Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D054464:Peroxiredoxins; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D025801:Ubiquitin / Q000187:drug effects* / Q000378:metabolism; D051844:alpha-Synuclein / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007306:Insecticides; D015513:Oncogene Proteins; D025801:Ubiquitin; D051844:alpha-Synuclein; D012402:Rotenone; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D046988:Proteasome Endopeptidase Complex; D042967:Electron Transport Complex I