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Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. | LitMetric

AI Article Synopsis

  • Parkinson's disease (PD) is linked to the loss of dopamine-producing neurons, and exposure to pesticides, like the fungicide benomyl, may increase the risk of developing PD.* -
  • Benomyl is metabolized into a compound that inhibits aldehyde dehydrogenase (ALDH), causing harmful build-up of a dopamine metabolite (DOPAL) that damages dopaminergic neurons.* -
  • Evidence from mouse studies, primary neuron experiments, and zebrafish models, along with epidemiological findings, supports the idea that benomyl exposure contributes to PD by selectively harming dopamine neurons.*

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545765PMC
http://dx.doi.org/10.1073/pnas.1220399110DOI Listing

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