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Environmental Factor, February 2013

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Exploring the haunting legacy – benomyl and Parkinson’s

By Sheila Yong

Arthur Fitzmaurice, Ph.D.

Fitzmaurice is a postdoctoral scholar working in the Bronstein group under an NIEHS training grant. (Photo courtesy of Randy Guiaya)

Jeff Bronstein, M.D., Ph.D.

Bronstein is a professor of molecular toxicology and neurology and is director of the Movement Disorders Program at UCLA. (Photo courtesy of UCLA)

More than a decade after the use of the fungicide benomyl was discontinued in the U.S., its toxic effects are still fresh in the minds of an interdisciplinary team of researchers at the University of California, Los Angeles (UCLA). Their latest NIEHS-funded research reports on the discovery of a mechanism involved in Parkinson’s disease (PD) that results in the inhibition of a key enzyme in the brain and may offer insight into a novel treatment approach.

In a study published in the Jan. 8 edition of the journal Proceedings of the National Academy of Sciences, the researchers reported that benomyl exposure results in damage of the dopaminergic neurons in the brain. The study was led by senior author Jeff Bronstein, M.D., Ph.D., whose laboratory is part of the NIEHS Centers for Neurodegeneration Science (CNS) program.

Researchers at the CNS at UCLA have been devoting their efforts to uncovering the link between pesticides and the pathologies of PD. They had previously found an association between pesticide exposure and increased risk of PD in a well-established patient cohort in the agricultural region of California’s Central Valley. Besides conducting epidemiological studies involving human subjects, the researchers also utilized cell culture and animal models to dissect the mechanisms involved in PD development.

Not just a genetic problem

As the name implies, dopaminergic neurons are the main source of the neurotransmitter dopamine. These neurons are important in many brain functions, including voluntary movement and a variety of behavioral processes. Damage to these neurons is often associated with PD.

While research on PD has revealed genetic mutations that contribute to the inherited form of the disease, these mutations only account for a small fraction of disease occurrence, said first author of the study and a postdoctoral scholar in Bronstein’s laboratory Arthur Fitzmaurice, Ph.D., in a UCLA press release. “As a result, environmental factors almost certainly play an important role in this disorder. Understanding the relevant mechanisms, particularly what causes the selective loss of dopaminergic neurons, may provide important clues to explain how the disease develops,” he added. One such environmental factor is the wide use in the 1970s of benomyl, which has the potential to cause liver tumors, brain malformations, reproductive defects, and carcinogenesis.

To establish a direct causal relationship between benomyl and PD, the researchers turned to primary neuronal cultures and zebrafish embryos to see if benomyl could cause any of the PD pathologies in these experimental systems. They found that benomyl selectively damaged the dopaminergic neurons, while leaving the other neurons unscathed. Interestingly, the researchers also observed a swimming deficit in zebrafish exposed to benomyl, suggesting that the loss of dopaminergic neurons resulted in impaired voluntary movement in these organisms.

An inhibited enzyme points to a potential target for treatment

Based on their previous finding that benomyl inhibits aldehyde dehydrogenase (ALDH) activity in mouse mitochondria, the authors sought to determine if ALDH activity was also inhibited in benomyl-treated primary neurons. Through fluorescence-based enzyme activity measurements, they found that benomyl inhibited ALDH activity in the neurons and its effect was concentration-dependent.

ALDH is required to metabolize dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is toxic to the brain and has been proposed to contribute to PD development. Hence, the authors proposed that ALDH inhibition and the subsequent accumulation of DOPAL lead to an increased risk in developing PD.

This study unveils a novel mechanism for PD development, which involves the inhibition of ALDH, making it potentially a novel target for drug therapy, according to Bronstein. The authors did not observe any connection between benomyl exposure and accumulation of alpha-synuclein, which, until now, had been considered the central driver of PD pathogenesis.

More importantly, findings from this study reinforce the authors’ hypothesis that pesticides may be partially responsible for the high PD occurrence rates among farmers and others in rural areas. “The discovery of this new pathway may be a new avenue for developing therapeutic drugs,” Bronstein said.

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. 2013. Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci U S A. 110(2):636-641.

(Sheila Yong, Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction.)

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