RT Journal Article
SR Electronic
T1 Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease
JF Neurology
JO Neurology
FD Lippincott Williams & Wilkins
SP 419
OP 426
DO 10.1212/WNL.0000000000000083
VO 82
IS 5
A1 Arthur G. Fitzmaurice
A1 Shannon L. Rhodes
A1 Myles Cockburn
A1 Beate Ritz
A1 Jeff M. Bronstein
YR 2014
UL http://n.neurology.org/content/82/5/419.abstract
AB 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.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