Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system.
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.
Betarbet
Ranjita
R
Center for Neurodegenerative Disease, Center for Neurodegenerative diseases, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA. rbetarb@emory.edu
Canet-Aviles
Rosa M
RM
Sherer
Todd B
TB
Mastroberardino
Pier G
PG
McLendon
Chris
C
Kim
Jin-Ho
JH
Lund
Serena
S
Na
Hye-Mee
HM
Taylor
Georgia
G
Bence
Neil F
NF
Kopito
Ron
R
Seo
Byoung Boo
BB
Yagi
Takao
T
Yagi
Akemi
A
Klinefelter
Gary
G
Cookson
Mark R
MR
Greenamyre
J Timothy
JT
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
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