Mechanism for Increased Parkinson’s Disease Risk from Benomyl Exposure
Jeff Bronstein, M.D., Ph.D., Beate Ritz, M.D., Ph.D, Aaron Lulla
University of California, Los Angeles
NIEHS Grants P01ES016732, R01ES010544, R21ES016446, U54ES012078, T32ES015457
NIEHS grantees integrated findings from cell, animal, and population studies to reveal how exposure to the fungicide benomyl increases risk for Parkinson's disease. Their work suggests that the neurodegenerative process by which benomyl acts might also occur in people with Parkinson’s disease who were not exposed to benomyl.
Benomyl was discontinued in the U.S. in 2001 but is still used in some countries. The researchers’ population studies indicated an association between higher exposure to benomyl and increased Parkinson’s disease risk. They tested the effects of benomyl on cell cultures, finding that the fungicide inhibited aldehyde dehydrogenase (ALDH) activity and altered dopamine levels. Cell culture experiments and tests using a zebrafish model of Parkinson’s disease showed that benomyl brought on selective loss of dopamine-producing neurons while not affecting other types of neurons. The cell loss decreased when the researchers added an enzyme that reduced the formation of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a reactive dopamine metabolite.
These results, together with those from previous studies, provide evidence for a Parkinson’s disease pathway in which benomyl inhibits ALDH, leading to DOPAL accumulation and degeneration of dopamine-producing neurons. This ALDH pathway may explain why dopamine-producing neurons are selectively vulnerable in Parkinson’s disease and could also provide a new target for therapeutic drugs.
Citation: Fitzmaurice AG, Rhodes SL, Lulla A, Murphy NP, Lam HA, O'Donnell KC, Barnhill L, Casida JE, Cockburn M, Sagasti A, Stahl MC, Maidment NT, Ritz B, Bronstein JM. 2012 Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci U S A 110(2):636-641.
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