Summary: A new UCLA study clarifies how the fungicide ziram triggers loss of the brain’s primary dopamine source and points to a possible protective strategy.
Source: UCLA.
Exposure to a class of widely used pesticides called dithiocarbamates has been linked to an increased risk of Parkinson’s disease, but the precise way these compounds damage the brain has not been fully understood. A new study from UCLA identifies key steps in that process for the fungicide ziram and suggests a therapeutic approach that may help protect neurons and slow disease progression.
The research targeted ziram, a fungicide commonly applied in intensive agricultural regions such as California’s Central Valley. The study shows ziram causes loss of dopaminergic neurons, the brain cells that produce dopamine and whose degeneration is a hallmark of Parkinson’s disease.
According to the study, ziram increases levels of the brain protein α-synuclein. Elevated α-synuclein tends to misfold and aggregate into clumps that damage neighboring neurons. This pattern of α-synuclein accumulation and aggregation also appears in idiopathic Parkinson’s disease, making the protein a central focus for therapies aimed at slowing or halting neurodegeneration.
Using zebrafish as an experimental model, researchers tested whether removing or disrupting α-synuclein could prevent the neuronal damage caused by ziram. When the team genetically eliminated α-synuclein in zebrafish, the animals were protected from ziram-induced loss of dopamine neurons and retained normal swimming behavior that otherwise deteriorated following exposure.
The investigators also evaluated an experimental compound, CLRO1, developed at UCLA, which disassembles α-synuclein aggregates. Treating zebrafish with CLRO1 after ziram exposure prevented the Parkinson’s-like motor deficits and neuronal loss observed in untreated fish. These results indicate two effective strategies in this model: preventing accumulation of α-synuclein genetically or breaking up toxic aggregates pharmacologically.
“Eliminating the protein genetically or dissolving its aggregates with this compound prevented ziram toxicity,” said Jeff Bronstein, study lead author, professor of neurology and director of movement disorders at the David Geffen School of Medicine at UCLA. “This work links environmental toxins to the same pathogenic pathway active in genetically susceptible individuals and supports using aggregate-targeting drugs for patients whose Parkinson’s was triggered by pesticide exposure.”
The study, published June 15 in the peer-reviewed journal Environmental Health Perspectives, established the first zebrafish model of pesticide-linked Parkinson’s-like neurodegeneration to test environmental and pharmacological interventions. In this model, zebrafish exposed to ziram developed motor impairments and sustained loss of dopaminergic neurons consistent with Parkinson’s-like pathology.
After confirming that genetic removal of α-synuclein protected zebrafish from ziram’s effects, the researchers administered CLRO1 to fish that had intact α-synuclein. CLRO1 disrupted α-synuclein aggregates and likewise prevented the behavioral deficits and neuronal loss induced by ziram exposure. These complementary approaches strengthen the conclusion that α-synuclein aggregation is a required step in ziram-mediated neurotoxicity.
Looking ahead, the UCLA team plans to investigate whether other environmental agents use the same α-synuclein–driven pathway to cause neuronal damage. They will also continue preclinical development of CLRO1 and other aggregate-targeting compounds with the goal of advancing to clinical trials in humans.
Bronstein notes the potential clinical importance of these findings: roughly 70 percent of Parkinson’s cases cannot be explained solely by genetics, so identifying environmental mechanisms and treatments could benefit a large proportion of patients whose disease is linked to exposures rather than inherited mutations.
Funding: Research funding was provided by the NIH/National Institute of Environmental Health Sciences.
Source: Kim Irwin – UCLA
Image Source: Image credited to Stephan Moratti.
Original Research: Full open access research titled “Organophosphate Pesticide Exposures, Nitric Oxide Synthase Gene Variants, and Gene–Pesticide Interactions in a Case–Control Study of Parkinson’s Disease, California (USA)” by Kimberly C. Paul, Janet S. Sinsheimer, Shannon L. Rhodes, Myles Cockburn, Jeff Bronstein, and Beate Ritz in Environmental Health Perspectives. Published online May 2016. DOI: 10.1289/EHP.1408976
MLA: UCLA. “A Protective Strategy Against Pesticide-Linked Parkinson’s Disease.” NeuroscienceNews, 15 June 2016.
APA: UCLA. (2016, June 15). A Protective Strategy Against Pesticide-Linked Parkinson’s Disease. NeuroscienceNews. Retrieved June 15, 2016.
Chicago: UCLA. “A Protective Strategy Against Pesticide-Linked Parkinson’s Disease.” NeuroscienceNews. (accessed June 15, 2016).
Abstract
Organophosphate Pesticide Exposures, Nitric Oxide Synthase Gene Variants, and Gene–Pesticide Interactions in a Case–Control Study of Parkinson’s Disease, California (USA)
Background: Nitric oxide synthase (NOS) genes are candidates for Parkinson’s disease risk because NOS enzymes produce nitric oxide (NO), a pro-oxidant capable of damaging neurons. Widely used organophosphate (OP) pesticides can induce oxidative stress and have been associated with elevated PD risk. Variants in the PON1 (paraoxonase 1) gene influence the ability to metabolize OPs.
Objective: This study investigated contributions of NOS gene variants and OP pesticide exposures to PD risk while accounting for PON1 status.
Methods: The case–control analysis included 357 incident PD cases and 495 population controls. Researchers examined eight NOS single nucleotide polymorphisms (SNPs) and their interactions with both household and ambient agricultural OP exposures assessed using geographic information system (GIS) methods.
Results: The analysis suggested an elevated adjusted odds ratio for PD among homozygous variant carriers of NOS2A rs1060826. Significant interactions were found between NOS1 variants (for example, rs2682826) and OP exposures: participants carrying certain NOS1 genotypes who also experienced frequent OP exposures had substantially higher PD odds than those with neither risk factor. Similar interaction patterns were observed for ambient OP exposure and for multiple NOS1 SNPs, and a composite genetic risk score combining NOS1 SNPs also reached statistical significance.
Conclusions: These results indicate that OP pesticides are more strongly associated with Parkinson’s disease among individuals with variant NOS1 genotypes, supporting a role for oxidative stress–related mechanisms. The data provide evidence that NOS1 variants modify PD risk in populations exposed to organophosphate pesticides.