Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published January 8, 2013 | Supplemental Material + Published
Journal Article Open

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

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.

Additional Information

© 2013 National Academy of Sciences. Contributed by John E. Casida, November 27, 2012; Sent for review October 19, 2012. Published online before print December 24, 2012. We thank Dr. Neil Harris for use of the Zeiss LSM 5 Pascal microscope. This work was funded in part by National Institute of Environmental Health Sciences Grants P01ES016732, R01ES010544, 5R21ES16446-2, and U54ES012078; National Institute of Neurological Disorders and Stroke Grant NS038367; the Veterans Affairs Healthcare System(Southwest Parkinson's Disease Research, Education, and Clinical Center); the Michael J. Fox Foundation; the Levine Foundation; and the Parkinson Alliance. A.G.F. was supported in part by a National Defense Science and Engineering Graduate Fellowship and US Department of Health and Human Services Ruth L. Kirschstein Institutional National Research Service Award T32ES015457 in Molecular Toxicology (to the University of California, Los Angeles). Author contributions: A.G.F., S.L.R., J.E.C., B.R., and J.M.B. designed research; A.G.F., S.L.R., A.L., N.P.M., H.A.L., K.C.O., and M.C.S. performed research; J.E.C., M.C., and A.S. contributed new reagents/analytic tools; A.G.F., S.L.R., N.P.M., L.B., and N.T.M. analyzed data; and A.G.F., S.L.R., J.E.C., and J.M.B. wrote the paper. The authors declare no conflict of interest.

Attached Files

Published - PNAS-2013-Fitzmaurice-636-41.pdf

Supplemental Material - pnas.201220399SI.pdf

Files

PNAS-2013-Fitzmaurice-636-41.pdf
Files (1.1 MB)
Name Size Download all
md5:5445b0208f71ff65a6a6cff5ce06b312
1.1 MB Preview Download
md5:4718dec55c87317bf9441c85f18f5a13
38.7 kB Preview Download

Additional details

Created:
August 19, 2023
Modified:
October 23, 2023