title: Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease.
abstract: Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, USA.
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Fitzmaurice
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rhodes
authors.forename: Aaron
authors.initials: A
authors.lastname: Lulla
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
authors.forename: Hoa A
authors.initials: HA
authors.lastname: Lam
authors.forename: Kelley C
authors.initials: KC
authors.lastname: O'Donnell
authors.forename: Lisa
authors.initials: L
authors.lastname: Barnhill
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
authors.forename: Myles
authors.initials: M
authors.lastname: Cockburn
authors.forename: Alvaro
authors.initials: A
authors.lastname: Sagasti
authors.forename: Mark C
authors.initials: MC
authors.lastname: Stahl
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Bronstein
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001542:Benomyl / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005434:Flow Cytometry; D005659:Fungicides, Industrial / Q000633:toxicity*; D006801:Humans; D016015:Logistic Models; D008636:Mesencephalon / Q000166:cytology; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced; D016017:Odds Ratio; D010300:Parkinson Disease / Q000201:enzymology / Q000453:epidemiology* / Q000209:etiology* / Q000503:physiopathology*; D051381:Rats; D015027:Zebrafish
chemical_list: D005659:Fungicides, Industrial; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D000444:Aldehyde Dehydrogenase; D001542:Benomyl