Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system

Neurobiol Dis. 2006 May;22(2):404-20. doi: 10.1016/j.nbd.2005.12.003. Epub 2006 Jan 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / physiology
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Humans
  • Insecticides / toxicity
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Nerve Degeneration / chemically induced*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Oncogene Proteins / drug effects*
  • Oncogene Proteins / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Parkinsonian Disorders / chemically induced*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology
  • Peroxiredoxins
  • Proteasome Endopeptidase Complex / drug effects*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Deglycase DJ-1
  • Rats
  • Rats, Inbred Lew
  • Rotenone / toxicity*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / physiopathology
  • Ubiquitin / drug effects*
  • Ubiquitin / metabolism
  • alpha-Synuclein / drug effects*
  • alpha-Synuclein / metabolism

Substances

  • Insecticides
  • Oncogene Proteins
  • Ubiquitin
  • alpha-Synuclein
  • Rotenone
  • Peroxiredoxins
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Proteasome Endopeptidase Complex
  • Electron Transport Complex I