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February 04, 2014; 82 (5) Article

Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease

Arthur G. Fitzmaurice, Shannon L. Rhodes, Myles Cockburn, Beate Ritz, Jeff M. Bronstein
First published February 3, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000083
Arthur G. Fitzmaurice
From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles; Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles; Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles; and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
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Shannon L. Rhodes
From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles; Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles; Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles; and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
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Myles Cockburn
From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles; Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles; Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles; and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
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Beate Ritz
From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles; Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles; Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles; and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
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Jeff M. Bronstein
From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles; Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles; Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles; and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
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Citation
Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease
Arthur G. Fitzmaurice, Shannon L. Rhodes, Myles Cockburn, Beate Ritz, Jeff M. Bronstein
Neurology Feb 2014, 82 (5) 419-426; DOI: 10.1212/WNL.0000000000000083

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This article has a correction. Please see:

  • Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease - November 11, 2014
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Abstract

Objective: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study.

Methods: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation.

Results: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides.

Conclusion: ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression.

GLOSSARY

ALDH=
aldehyde dehydrogenase;
ALDH2=
aldehyde dehydrogenase 2 family (mitochondrial);
CI=
confidence interval;
DOPAL=
3,4-dihydroxyphenylacetaldehyde;
PD=
Parkinson disease;
SNP=
single nucleotide polymorphism;
UCLA=
University of California, Los Angeles

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at www.neurology.org

  • Received June 27, 2013.
  • Accepted in final form October 25, 2013.
  • © 2014 American Academy of Neurology
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Letters: Rapid online correspondence

  • Response to Dr. Burke's comments
    • Jeff M Bronstein, Professor, David Geffen School of Medicine at UCLAjbronste@mednet.ucla.edu
    • Jeff M Bronstein and Arthur Fitzmaurice, Los Angeles, CA
    Submitted June 02, 2014
  • Request for Correction to "Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease" by Fitzmaurice et al.
    • William J. Burke, Professor Emeritus, Saint Louis University Medical Schoolburkewj@slu.edu
    • St Louis, MO
    Submitted May 22, 2014
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