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UPMC Researchers Get Funding to Study Link between Pesticides and Parkinson's Disease

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NEW YORK (GenomeWeb) — Researchers at the University of Pittsburgh Medical Center have received funding to begin translating animal studies linking environmental toxin exposure and Parkinson's disease pathology to human samples. The funding was awarded by the National Institute of Environmental Health Sciences and totals $446,200, adding to about $1.5 million already awarded to this project.

Led by J. Timothy Greenamyre in the department of neurology at UPMC, the research will use a quantitative PCR method to detect mitochondrial DNA damage caused by exposure to pesticides such as rotenone and paraquat. The new funding enables evaluation of banked human blood samples obtained from different movement disorder centers in the US.

Laurie Sanders, an assistant professor leading the translational project in the Greenamyre lab, told PCR Insider this week that the award was the result of a special request for applications to build translational projects based on already funded grants.

The Greenamyre lab previously pioneered a rat model of pesticide-induced mtDNA damage. "We expose rats to the pesticide rotenone, and [find that] it interferes with complex I of the mitochondria," Sanders said. "We give it systemically, and the rats mimic features of human PD."

The group subsequently reached out to medical epidemiologists Caroline Tanner and Sam Goldman at the Parkinson's Institute in Sunnyvale, Calif. "They started to look and see whether there was an increased risk [of PD] with rotenone [exposure], and that is what they found," said Sanders.

Indeed, Tanner and Goldman showed that the risk of PD more than doubled in farmers exposed to rotenone or paraquat, according to the grant abstract.

The new funding now allows pairing of these epidemiological data sets with the qPCR evaluation of mtDNA damage in banked blood samples from people exposed to paraquat or rotenone, some of whom went on to develop PD.

"The mitochondria seem to be very important in terms of the pathogenesis of PD, and these particular pesticides are known to interfere with mitochondrial function," Sanders explained.

Ben Van Houten, a researcher who joined UPMC from NIEHS in 2008, developed the qPCR method now used in the Greenamyre lab.

The method allows extraction of both mitochondrial and genomic DNA at the same time. "We don't have to expose the DNA to any sort of artificial damage [caused by] the extraction process," Sanders said.

"The idea behind it is that when the polymerase encounters a type of lesion or damage, it is blocked and stopped. ... If you have a sample that's damaged, due to a toxin or otherwise, you're going to get less PCR product," she said. The resulting increase in experimentally measured cycle threshold allows quantification of the extent of DNA damage.

The qPCR method was recently described in detail in a chapter in Molecular Toxicology Protocols. In an email to PCR Insider, Van Houten said his group has now published more than 25 articles using this approach. In one of the first, he "developed the hypothesis that [reactive oxygen species] damaged mitochondrial DNA more than nuclear DNA," he said. "This has turned out right, and is probably due to the fact mitochondria build [iron-sulfur clusters] and therefore have high levels of iron close to mtDNA to promote Fenton chemistry."

Van Houten, a professor of molecular oncology at UPMC, said that there are two patents on the method. One covers the method generally, while a second covers its application for predicting atherosclerotic heart disease.

In 2008, the mtDNA damage-detecting qPCR method was licensed to Transgenomic, Van Houten noted. That company signed a licensing option agreement with Gene Solutions in 2009 for a set of validated mutations that could form the basis for a diagnostic test for Parkinson's disease. As covered in GWDN at the time, under the agreement the companies would evaluate the ability of Transgenomic's mitochondrial mutation-detection technology to detect and quantify the presence of the low-level mtDNA mutations shown to be present in Parkinson's disease patients.

However, UPMC researchers could not comment on whether they are currently collaborating with Transgenomic.

The link between pesticide exposure and Parkinson's has been suggested in numerous epidemiological studies. However, the mechanisms whereby toxin exposure could lead to cell death in specific brain regions many years later remain to be elucidated. Sanders explained that the Greenamyre lab has recently published other work supporting the idea that mitochondrial damage may be the critical player.

In one recent study, they demonstrated mtDNA damage in postmortem brain tissue from people with PD, specifically a type of damage called abasic sites. A second recent study examined the LRRK2 mutation, a genetic form of PD, in induced pluripotent stem cell-derived neural cells, and showed this led to an increase in mtDNA damage. "So, this [mtDNA mechanism] may also extend to genetic forms of Parkinson's disease," Sanders said.

The group has recently correlated mtDNA damage in blood with brain biomarkers in rotenone-exposed rats, Sanders said. The lab has also already validated that the qPCR method works in the banked blood samples. "We're in the early days of the study," she said, "but we're optimistic about our preliminary results."

The lab is also collaborating with commercial entities, "evaluating whether or not we can use this as a screening tool ... and [working] to scale up this particular assay so that it would be a better platform for our industry partners," Sanders said, but she was not at liberty to disclose the particular parties at this time.

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