Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

Arthur G. Fitzmaurice, Shannon L. Rhodes, Aaron Lulla, Niall P. Murphy, Hoa A. Lam, Kelley C. O'Donnell, Lisa Barnhill, John E. Casida, Myles Cockburn, Alvaro Sagasti, Mark C. Stahl, Nigel T. Maidment, Beate Ritz, Jeff M. Bronstein

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associatedwith 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.

Original languageEnglish (US)
Pages (from-to)636-641
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number2
DOIs
StatePublished - Jan 8 2013

All Science Journal Classification (ASJC) codes

  • General

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