Fitzmaurice, A.G., Rhodes, S.L., Lulla, A., Murphy, N.P., Lam, H.A., O'Donnell, K.C., Barnhill, L., Casida, J.E., Cockburn, M., Sagasti, A., Stahl, M.C., Maidment, N.T., Ritz, B., and Bronstein, J.M. (2013) Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America. 110(2):636-641.
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.