Summary: A University of Guelph study shows that low-level exposure to two widely used agricultural pesticides, paraquat and maneb, can interact with genetic predisposition to sharply increase the risk of Parkinson’s disease by disrupting mitochondrial transport in neurons.
Source: University of Guelph
New research clarifies how exposure to common pesticides can raise the likelihood of Parkinson’s disease in susceptible people.
Multiple epidemiological studies have linked exposure to the agrochemicals paraquat and maneb with a higher incidence of Parkinson’s disease. Researchers at the University of Guelph have now shown a cellular mechanism that helps explain this association.
Professor Scott Ryan and his team found that low-level exposure to paraquat and maneb disrupts intracellular transport in dopaminergic neurons in a way that mimics changes caused by known Parkinson’s-linked mutations. When these chemical effects combine with genetic susceptibility, the result is a sharply increased risk of disease onset.
“People exposed to these chemicals are at about a 250 percent higher risk of developing Parkinson’s disease than the general population,” said Scott Ryan, professor in the Department of Molecular and Cellular Biology. “We set out to understand what happens inside human neurons that makes some people develop the disease while others do not.”
Paraquat and maneb are used together in many agricultural settings: paraquat is often applied during crop growth and maneb helps prevent post-harvest spoilage. Previous evidence linking these pesticides to Parkinson’s came largely from animal studies and population-level analyses showing higher rates among farmers and agricultural workers. This study is among the first to examine how these agrochemicals affect human neurons at the cellular level.
The team used human pluripotent stem cells to produce dopamine-producing neurons—the specific cell type lost in Parkinson’s disease. They compared neurons derived from patients carrying a Parkinson’s-associated mutation in the alpha-synuclein gene (SNCA-A53T) with genetically matched control cells in which the mutation had been corrected, and with normal embryonic stem cell–derived neurons that were gene-edited to carry the same risk mutation.
When exposed to paraquat and maneb at low concentrations, neurons carrying the SNCA-A53T mutation showed impaired transport of mitochondria along axons. The mitochondria failed to reach regions of the neuron that require energy, leaving vulnerable neurons energy-deprived and functionally impaired. These effects occurred at doses below the Environmental Protection Agency’s lowest reported observed effect level for these chemicals. By contrast, non-mutant neurons required higher doses before similar damage occurred.
At the molecular level, the researchers discovered that exposure to these mitochondrial toxins triggered production of nitric oxide (NO), which then caused nitration of alpha-tubulin in the microtubule cytoskeleton. Nitration of microtubules reduced their ability to associate with key transport proteins, including alpha-synuclein and the motor protein kinesin-5B. The result was an arrest of anterograde mitochondrial transport—the movement of mitochondria from the cell body toward synapses and energy-demanding regions.
Importantly, inhibiting nitric oxide synthesis with a nitric oxide synthase (NOS) inhibitor restored mitochondrial transport, indicating that NO-mediated nitration is a critical step in this process. These findings point to a gene-by-environment interaction: the SNCA-A53T mutation makes neurons more vulnerable to pesticide-induced nitration of microtubules, which compromises mitochondrial trafficking and neuronal energy supply.
“Our data show that not everyone is equally protected by current safety standards,” Ryan said. “People with an underlying genetic risk for Parkinson’s disease appear to be harmed by pesticide exposures at levels previously considered safe. This suggests regulatory thresholds for these chemicals should be reassessed to protect those who are more susceptible.”
Source: Prof. Scott Ryan, University of Guelph
Publisher: Organized by NeuroscienceNews.com
Image source: NeuroscienceNews.com (public domain)
Original research: Abstract for “Nitration of microtubules blocks axonal mitochondrial transport in a human pluripotent stem cell model of Parkinson’s disease,” published in FASEB Journal. DOI: 10.1096/fj.201700759RR
The study used a patient-derived stem cell model to compare dopaminergic neurons carrying the SNCA-A53T mutation with isogenic mutation-corrected controls. Exposure to rotenone or the paraquat/maneb combination led mutant neurons to produce nitric oxide, which nitrated alpha-tubulin in microtubules. Nitration disrupted the binding of alpha-synuclein and kinesin-5B to microtubules, halting anterograde mitochondrial transport. Nitration occurred in the C-terminal domain of alpha-tubulin and was reversible by inhibition of nitric oxide synthesis. These results demonstrate a specific gene–environment interaction in Parkinson’s disease: agrochemical exposure selectively triggers a defect in mitochondrial transport in neurons carrying the SNCA-A53T mutation.
- Exposure to paraquat and maneb can increase Parkinson’s disease risk, especially in people with genetic vulnerability.
- Low-level pesticide exposure impairs mitochondrial transport in dopaminergic neurons by promoting nitration of microtubules.
- This mechanism links environmental toxins to cellular changes that resemble genetic causes of Parkinson’s disease.
- Current safety thresholds for these agrochemicals may not adequately protect genetically susceptible individuals.