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Intersecting pathways to neurodegeneration in parkinson's disease: Effects of the pesticide rotenone on dj-1, alpha-synuclein, and the ubiquitin-proteasome system

Academic Article
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Overview

authors

  • Betarbet, R.
  • Canet-Aviles, R. A.
  • Sherer, T. B.
  • Mastroberardino, P. G.
  • McLendon, C.
  • Kim, J. H.
  • Lund, S.
  • Na, H. M.
  • Taylor, G.
  • Bence, N. F.
  • Kopito, R.
  • Seo, B. B.
  • Yagi, Takao
  • Klinefelter, G.
  • Cookson, M. R.
  • Greenamyre, J. T.

publication date

  • May 2006

journal

  • Neurobiology of Disease  Journal

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.

subject areas

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

keywords

  • alpha-tocopherol
  • mitochondria
  • oxidative stress
  • pesticide
  • proteasomal dysfunction
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Identity

International Standard Serial Number (ISSN)

  • 0969-9961

Digital Object Identifier (DOI)

  • 10.1016/j.nbd.2005.12.003

PubMed ID

  • 16439141
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Additional Document Info

start page

  • 404

end page

  • 420

volume

  • 22

issue

  • 2

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