In a new article published in the journal Molecular Neurodegeneration, researchers at the University of Missouri School of Medicine take some of the first steps toward unraveling the molecular dysfunction that occurs when proteins are exposed to environmental toxins. Their discovery helps further explain recent NIH findings that demonstrate the link between Parkinson disease and 2 particular pesticides – rotenone and paraquat.
"Fewer than 5% of Parkinson's cases are attributed to genetics, but more than 95% of cases have unknown causes," said Zezong Gu MD PhD, assistant professor of pathology and anatomical sciences. "This study provides the evidence that oxidative stress, possibly due to sustained exposure to environmental toxins, may serve as a primary cause of Parkinson's. This helps us begin to unveil why many people, such as farmers exposed to pesticides, have an increased incidence of the disease."
Scientists previously understood that Parkinson disease is associated with oxidative stress, which is when electronically unstable atoms or molecules damage cells. The University of Missouri study yields more specific information about how oxidative stress causes parkin, a protein responsible for regulating other proteins, to malfunction.
These findings come as the result of collaborative research conducted by Gu and the paper's primary author, Fanjun Meng, an University of Missouri visiting scholar from the Chinese Academy of Sciences Beijing Institute of Genomics, as well as colleagues at the Sanford-Burnham Medical Research Institute and the University of California at San Diego. The article also represents the first published work from researchers at the new University of Missouri Center for Translational Neuroscience.
Gu and his team with his Burnham colleagues invented a new antibody that allowed them to detect how oxidative stress affected proteins when exposed to a variety of environmental toxins, such as the pesticide rotenone. They then specifically demonstrated how oxidative stress caused parkin proteins to cluster together and malfunction, rather than performing normally by cleaning up damaged proteins.
"This whole process progresses into Parkinson's disease," Gu said. "We illustrated the molecular events that lead to the more common form of the disorder in the vast majority of cases with unknown causes. Knowing this, we can find ways to correct, prevent and reduce the incidence of this disease."
Researchers used mass spectrometry to analyze findings. They measured parkin fragments, pinpointed whether the proteins were modified, and where that modification occurred. This enabled them to map the location of parkin oxidation and further compare these events with genetic mutations in patients with Parkinson disease reported in the literature. Their findings demonstrated that parkin protein oxidation in certain locations corresponds with the location of mutations. They then sought to determine the outcome of the modification – finding their results to be consistent in multiple disease models, including cell cultures and tissue samples from rodents, monkeys, and human postmortem Parkinson patients.
Gu and Meng hope to extend their investigation into preventive treatments and therapies through work at University of Missouri's Center for Botanical Interaction Studies.
Source: News Release
University of Missouri School of Medicine
June 22, 2011