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's disease and two particular pesticides -- rotenone and paraquat.
"Fewer than 5 percent of Parkinson's cases are attributed to genetics, but more than 95 percent 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's is associated with oxidative stress, which is when electronically unstable atoms or molecules damage cells. The MU 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 MU 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 MU Center for Translational Neuroscience.
Gu and his 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's 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's patients.
Gu and Meng hope to extend their investigation into preventive treatments and therapies through work at MU's Center for Botanical Interaction Studies. Created with a new $7.6 million grant from the National Institutes of Health, MU's center is one of five in the country selected to lead interdisciplinary and collaborative research on botanical dietary supplements.
After Alzheimer's disease, Parkinson's disease is the most common neurodegenerative disorder. Approximately 60,000 new cases of Parkinson's disease are diagnosed each year. By some estimates, at least one million people in the United States have the disease, which has no cure.
- Fanjun Meng, Dongdong Yao, Yang Shi, Jonathan Kabakoff, Wei Wu, Joshua Reicher, Yuliang Ma, Bernd Moosmann, Eliezer Masliah, Stuart A Lipton, Zezong Gu. Oxidation of the Cysteine-Rich Regions of Parkin Perturbs Its E3 Ligase Activity and Contributes to Protein Aggregation. Molecular Neurodegeneration, 2011; 6 (1): 34 DOI: 10.1186/1750-1326-6-34
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