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Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease.

http://www.ncbi.nlm.nih.gov/pubmed/23267077

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.

Pubmed ID: 23267077 RIS Download

Mesh terms: 3,4-Dihydroxyphenylacetic Acid | Aldehyde Dehydrogenase | Animals | Benomyl | Dopaminergic Neurons | Flow Cytometry | Fungicides, Industrial | Humans | Logistic Models | Mesencephalon | Mitochondria | Nerve Degeneration | Odds Ratio | Parkinson Disease | Rats | Zebrafish

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Associated grants

  • Agency: NIEHS NIH HHS, Id: 5R21ES16446-2
  • Agency: NINDS NIH HHS, Id: NS038367
  • Agency: NIEHS NIH HHS, Id: P01 ES016732
  • Agency: NIEHS NIH HHS, Id: P01ES016732
  • Agency: NIEHS NIH HHS, Id: R01 ES010544
  • Agency: NIEHS NIH HHS, Id: R01ES010544
  • Agency: NIGMS NIH HHS, Id: T32 GM008042
  • Agency: NIEHS NIH HHS, Id: T32ES015457
  • Agency: NIEHS NIH HHS, Id: U54 ES012078
  • Agency: NIEHS NIH HHS, Id: U54ES012078

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