期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 2, 页码 636-641出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220399110
关键词
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资金
- National Institute of Environmental Health Sciences [P01ES016732, R01ES010544, 5R21ES16446-2, U54ES012078]
- National Institute of Neurological Disorders and Stroke [NS038367]
- Veterans Affairs Healthcare System (Southwest Parkinson's Disease Research, Education, and Clinical Center)
- Michael J. Fox Foundation
- Levine Foundation
- Parkinson Alliance
- National Defense Science and Engineering Graduate Fellowship
- US Department of Health and Human Services Ruth L. Kirschstein Institutional National Research Service Award [T32ES015457]
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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