Chronic systemic pesticide exposure reproduces features of Parkinson's disease

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and α-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

[1]  R. Swerdlow,et al.  Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson's disease family , 1998, Annals of neurology.

[2]  J Q Trojanowski,et al.  Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. , 1998, The American journal of pathology.

[3]  William Slikker,et al.  Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration , 1997, Brain Research.

[4]  C. C. Johnson,et al.  The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living , 1998, Neurology.

[5]  W. Nicklas,et al.  Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. , 1985, Life sciences.

[6]  A. Torroni,et al.  Mitochondrial oxidative phosphorylation defects in parkinson's disease , 1991, Annals of neurology.

[7]  A H Schapira,et al.  Free radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors. , 1997, Brain research.

[8]  D. Price,et al.  A modified histochemical technique to visualize acetylcholinesterase-containing axons. , 1985, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[9]  D. Turnbull,et al.  MITOCHONDRIAL FUNCTION IN PARKINSON'S DISEASE , 1989, The Lancet.

[10]  J. Bonnar,et al.  Letter: Prostaglandins and pre-eclampsia. , 1974, Lancet.

[11]  A. Panov,et al.  Substrate specific effects of calcium on metabolism of rat heart mitochondria. , 1996, The American journal of physiology.

[12]  K. Hensley,et al.  Interaction of α‐Phenyl‐N‐tert‐Butyl Nitrone and Alternative Electron Acceptors with Complex I Indicates a Substrate Reduction Site Upstream from the Rotenone Binding Site , 1998, Journal of Neurochemistry.

[13]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[14]  M. Degli Esposti.  Inhibitors of NADH-ubiquinone reductase: an overview. , 1998, Biochimica et biophysica acta.

[15]  O. Hornykiewicz.  Dopamine (3-hydroxytyramine) and brain function. , 1966, Pharmacological reviews.

[16]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[17]  F. Condé,et al.  Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies , 2000, Neuroscience.

[18]  G. Petzinger,et al.  Experimental models of Parkinson's disease: insights from many models. , 1999, Laboratory animal science.

[19]  J. Langston,et al.  Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. , 1983, Science.

[20]  D. Mash,et al.  Immunochemical analysis of dopamine transporter protein in Parkinson's disease , 1997, Annals of neurology.

[21]  C. Marsden,et al.  Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. , 1992, Brain : a journal of neurology.

[22]  J W Langston,et al.  Parkinson disease in twins: an etiologic study. , 1999, JAMA.

[23]  J. Greenamyre,et al.  Polysynaptic regulation of glutamate receptors and mitochondrial enzyme activities in the basal ganglia of rats with unilateral dopamine depletion , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[25]  A. H. V. Schapira,et al.  MITOCHONDRIAL COMPLEX I DEFICIENCY IN PARKINSON'S DISEASE , 1989, The Lancet.

[26]  K. Tipton,et al.  Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds , 1993, Journal of neurochemistry.

[27]  G. Davey,et al.  Threshold Effects and Control of Oxidative Phosphorylation in Nonsynaptic Rat Brain Mitochondria , 1996, Journal of neurochemistry.

[28]  N. Sims.  Rapid Isolation of Metabolically Active Mitochondria from Rat Brain and Subregions Using Percoll Density Gradient Centrifugation , 1990, Journal of neurochemistry.

[29]  M. Lings,et al.  Articles , 1967, Soil Science Society of America Journal.

[30]  J. Parks,et al.  Abnormalities of the electron transport chain in idiopathic parkinson's disease , 1989, Annals of neurology.

[31]  J. Nutt,et al.  Environmental antecedents of young‐onset Parkinson's disease , 1993, Neurology.

[32]  J. Timothy Greenamyre,et al.  [3H]Dihydrorotenone Binding to NADH: Ubiquinone Reductase (Complex I) of the Electron Transport Chain: An Autoradiographic Study , 1996, The Journal of Neuroscience.

[33]  C. Marín,et al.  Mitochondria1 respiratory chain activity in skeletal muscle from patients with Parkinson's disease , 1993, Neurology.

[34]  B. Hyman,et al.  Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  F. Sharp,et al.  MK-801 reduces uptake and stimulates efflux of excitatory amino acids via membrane depolarization. , 1996, The American journal of physiology.

[36]  O. Blin,et al.  Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy , 1994, Journal of the Neurological Sciences.

[37]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[38]  A. Blackburn,et al.  Parkinson's disease, pesticides, and glutathione transferase polymorphisms , 1998, The Lancet.

[39]  B. Giasson,et al.  Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. , 2000, The Journal of biological chemistry.

[40]  M. Esposti.  Inhibitors of NADH-ubiquinone reductase: an overview. , 1998 .

[41]  E. Masliah,et al.  Role of Cytochrome c as a Stimulator of α-Synuclein Aggregation in Lewy Body Disease* , 1999, The Journal of Biological Chemistry.

[42]  J. Langston,et al.  Electron microscopy of Lewy bodies in the amygdala-parahippocampal region. Comparison with inclusion bodies in the MPTP-treated squirrel monkey. , 1996, Advances in neurology.

[43]  C. Marsden,et al.  Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease , 1989, Journal of neurochemistry.

[44]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[45]  J. Schulz,et al.  Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra , 1997, Brain Research.

[46]  B. Giasson,et al.  Dityrosine cross-linking promotes formation of stable α-synuclein polymers , 2000, Neurobiology of Aging.