Summary: A new study reports the combination of a toxic herbicide and lectins may trigger Parkinsonism after the toxins travel from the stomach to the brain.

Source: Penn State.

Combining low doses of a toxic herbicide with sugar-binding proteins called lectins may trigger Parkinsonism — symptoms typical of Parkinson’s disease like body tremors and slowing of body motions — after the toxin travels from the stomach to the brain.

In a study with rats, researchers at Penn State College of Medicine found that after ingesting paraquat, a once widely used herbicide that has been banned in the U.S. since 2007, along with lectins — sugar-binding proteins found widely in nature — the animals developed Parkinsonism.

According to Thyagarajan Subramanian, professor of neurology and neural and behavioral sciences and co-author on the study, the findings — recently published in the journal Parkinson’s Disease — offer clues to how and why Parkinson’s disease develops, and offer a model to test new medications in the future.

“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.”

The researchers were able to track the formation and spread of a misfolded protein called alpha-synuclein, which previous research has linked with Parkinson’s.

“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.”

R. Alberto Travagli, professor of neural and behavioral sciences and senior author of the study, said that while toxins like paraquat have been suspected of contributing to Parkinson’s for decades, the scientific evidence was small. While paraquat was linked with Parkinsonism in previous studies, those experiments typically used high doses of paraquat that humans were not likely to encounter in real life.

Additionally, lectins, which are used in medications to help deliver substances into the brain or stomach, also have been associated with certain rare forms of Parkinsonism. But the researchers weren’t sure if it was the lectins themselves that were causing Parkinsonism, or if they were helping different substances get into the body that then triggered the symptoms.

“Experimenting with the lectins together with the toxin makes sense, because lectins are used in pharmacology to chaperone other substances into the body,” Travagli said. “So it makes sense that the two can be combined and used to make the toxicity more potent, even though the amount of toxin is very low.”

Using a rat model, the researchers exposed the animals daily to small doses of paraquat and lectins for seven days. After stopping the treatment, the researchers waited two weeks. Then, the researchers did a variety of tests to measure problems with motor function and other symptoms typical of Parkinsonism.

The researchers observed a decrease in motor function that was consistent with Parkinsonism. But to confirm that the symptoms were related to Parkinsonism and not another cause, Travagli said he and the other researchers did several additional tests.

“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,” Travagli said. “We administered levodopa, which is a common medication for Parkinson’s disease. We saw a return to almost normal types of motor responses, which was a clear indication that we were looking at some sort of Parkinsonism.”

Additionally, the researchers said when the vagus nerve was disconnected from the stomach prior to exposure to paraquat and lectins, the animals were protected from Parkinsonism, confirming the route of the alpha-synuclein from the gut to the brain.

In the future, Travagli and Subramanian said they will explore whether interventions in the form of diet modifications or medications that interfere with the transport of alpha synuclein from the stomach via the vagus nerve could be used to help prevent or slow the development of Parkinsonism in this rat model. This includes a natural substance called squalamine which has been shown to remove alpha synuclein from the gut and is now in clinical trials for the certain symptoms associated with Parkinson’s disease.

Laura Anselmi, research associate; Cecilia Bove, doctoral student in neuroscience; F. Holly Coleman, lab manager; K. Le, research technologist; Megha Subramanian, research technologist; and Kala Venkiteswaran, assistant professor of neurology, also worked on this research.

Funding: This research was supported by the National Institutes of Health, the Michael J. Fox Foundation for Parkinson’s Disease and the Tobacco Settlement Fund.

Source: Katie Bohn – Penn State
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat” by L. Anselmi, C. Bove, F. H. Coleman, K. Le, M. P. Subramanian, K. Venkiteswaran, T. Subramanian & R. A. Travagli in Parkinson’s Disease. Published September 27 2018.
doi:10.1038/s41531-018-0066-0

Abstract

Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat

Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson’s disease (PD). We tested the hypothesis that gastric co-administration of subthreshold doses of lectins and paraquat can recreate the pathology and behavioral manifestations of PD in rats. A solution containing paraquat + lectin was administered daily for 7 days via gastric gavage, followed by testing for Parkinsonian behavior and gastric dysmotility. At the end of the experiment, brainstem and midbrain tissues were analyzed for the presence of misfolded α-synuclein and neuronal loss in the SNpc and in the dorsal motor nucleus of the vagus (DMV). Misfolded α-synuclein was found in DMV and SNpc neurons. A significant decrease in tyrosine hydroxylase positive dopaminergic neurons was noted in the SNpc, conversely there was no apparent loss of cholinergic neurons of the DMV. Nigrovagally-evoked gastric motility was impaired in treated rats prior to the onset of parkinsonism, the motor deficits of which were improved by L-dopa treatment. Vagotomy prevented the development of parkinsonian symptoms and constrained the appearance of misfolded α-synuclein to myenteric neurons. These data demonstrate that co-administration of subthreshold doses of paraquat and lectin induces progressive, L-dopa-responsive parkinsonism that is preceded by gastric dysmotility. This novel preclinical model of environmentally triggered PD provides functional support for Braak’s staging hypothesis of idiopathic PD.