Ingesting a once widely used herbicide called paraquat along with lectins — proteins in common foods that bind carbohydrates (e.g., sugars) — can lead to symptoms typical of Parkinson’s disease and known as parkinsonism, a study reported.
Importantly, this animal research provides a new preclinical model for testing treatments in forms of Parkinson’s disease influenced by environmental factors.
The study, “Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat,” was published in the journal Parkinson’s Disease.
Parkinson’s development in people has been linked to both genetic and environmental factors. Researchers need to model how these factors cause the disease to discover treatments for patients with different types of Parkinson’s.
Previous studies have modeled how high levels of individual neurotoxins and external factors such as diet are linked to Parkinson’s. But individuals, over the course of a lifetime, are more likely to be repeatedly exposed to low doses of toxins, or a combination of toxins, whose disease-causing capacity may be enhanced by factors that include diet.
For example, paraquat — a neurotoxin and herbicide once in wide use and still in restricted use in the U.S. though banned in Europe — has been linked to Parkinson’s disease (ways it can be ingested include drinking water). But it has only been studied in isolation and at doses far beyond those commonly encountered. Similarly, lectins — sugar-binding proteins commonly found in legumes and grains — have been linked with rare forms of parkinsonism.
For these reasons, researchers at Penn State College of Medicine sought to understand and model how repeated exposures to low doses of toxins and external factors contribute to Parkinson’s development. They sought to demonstrate how exposure to common levels of paraquat and lectin can induce disease symptoms.
The researchers applied low-level doses of paraquat and lectins to rats daily for a week, and after a couple of weeks, checked for symptoms of parkinsonism. They tested the animals for motor function and for the production of a misfolded protein called alpha-synuclein that is linked with the development of Parkinson’s disease. They detected a decrease in motor function and in the number of dopaminergic neurons (those that produce the brain signaling chemical dopamine), the generation of misfolded alpha-synuclein, and other symptoms typical of parkinsonism.
To confirm that the symptoms spotted were related to parkinsonism, the researchers performed tests to see if known Parkinson’s treatments — levodopa — could reverse the observed symptoms.
“After observing that these animals did indeed show symptoms of Parkinsonism, we wanted to double check and make sure we weren’t looking at animals that had these symptoms for another reason,” Thyagarajan Subramanian, a study co-author and professor of neurology at Penn State College of Medicine, said in a press release. “We administered levodopa … [and] saw a return to almost normal types of motor responses, which was a clear indication that we were looking at some sort of Parkinsonism.”
Increasing evidence suggests that environmental neurotoxins or misfolded alpha-synuclein proteins are transported from the gut to the brain through the vagus nerve — the nerve that enables communication between the gut and the brain— this way damaging dopaminergic neurons in the substantia nigra, a major brain region affected in Parkinson’s disease.
“We were able to demonstrate that if you have oral paraquat exposure, even at very low levels, and you also consume lectins — perhaps in the form of uncooked vegetables, dairy or eggs — then it could potentially trigger the formation of this protein alpha-synuclein in the gut,” Subramanian said. “Once it’s formed, it can travel up the vagus nerve and to the part of the brain that triggers the onset of Parkinson’s disease.”
Interestingly, removing the vagus nerve before exposing the animals to paraquat and lectins protected them from parkinsonism.
The researchers plan to test whether medical treatments or dietary modifications can interfere with the transport of alpha-synuclein from the gut to the brain via the vagus nerve in this new model of Parkinson’s incorporating environmental factors.
They intend to test a substance called squalamine, which has been shown to remove alpha-synuclein from the gut and is now in clinical trials for treating Parkinson’s symptoms.
“This study gives solid evidence that lectins, while in the presence of certain toxins, may be one potential culprit for the cause of Parkinsonism,” Subramanian said. “Additionally, this animal model can be a tool in the future to continue developing new medications and treatments for Parkinson’s disease.”