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
