Navigation Links
Genetic mutation increases risk of Parkinson's disease from pesticides
Date:11/27/2013

LA JOLLA, Calif., and CAMBRIDGE, Mass., November 27, 2013 A team of researchers has brought new clarity to the picture of how gene-environmental interactions can kill nerve cells that make dopamine. Dopamine is the neurotransmitter that sends messages to the part of the brain that controls movement and coordination. Their discoveries, described in a paper published online in Cell today, include identification of a molecule that protects neurons from pesticide damage.

"For the first time, we have used human stem cells derived from Parkinson's disease patients to show that a genetic mutation combined with exposure to pesticides creates a 'double hit' scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death," said Stuart Lipton, M.D., Ph.D., professor and director of Sanford-Burnham Medical Research Institute's Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study.

Until now, the link between pesticides and Parkinson's disease was based mainly on animal studies and epidemiological research that demonstrated an increased risk of disease among farmers, rural populations, and others exposed to agricultural chemicals.

In the new study, Lipton, along with Rajesh Ambasudhan, Ph.D., research assistant professor in the Del E. Webb Center, and Rudolf Jaenisch, M.D., founding member of Whitehead Institute for Biomedical Research and professor of biology at the Massachusetts Institute of Technology, used skin cells from Parkinson's patients that had a mutation in the gene encoding a protein called alpha-synuclein. Alpha-synuclein is the primary protein found in Lewy bodiesprotein clumps that are the pathological hallmark of Parkinson's disease.

Using patient skin cells, the researchers created human induced pluripotent stem cells (hiPSCs) containing the mutation, and then "corrected" the alpha-synuclein mutation in other cells. Next, they reprogrammed all of these cells to become the specific type of nerve cell that is damaged in Parkinson's disease, called A9 dopamine-containing neuronsthus creating two sets of neuronsidentical in every respect except for the alpha-synuclein mutation.

"Exposing both normal and mutant neurons to pesticidesincluding paraquat, maneb, and rotenonecreated excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death," said Frank Soldner, M.D., research scientist in Jaenisch's lab and co-author of the study.

"In fact, we observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels," said Scott Ryan, Ph.D., researcher in the Del E. Webb Center and lead author of the paper.

Having access to genetically matched neurons with the exception of a single mutation simplified the interpretation of the genetic contribution to pesticide-induced neuronal death. In this case, the researchers were able to pinpoint how cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathwaycalled MEF2C-PGC1alphathat normally protects neurons that contain dopamine. The free radicals attacked the MEF2C protein, leading to the loss of function of this pathway that would otherwise have protected the nerve cells from the pesticides.

"Once we understood the pathway and the molecules that were altered by the pesticides, we used high-throughput screening to identify molecules that could inhibit the effect of free radicals on the pathway," said Lipton. "One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, our findings may have potential clinical implications for repurposing these drugs to treat Parkinson's."

While the study clearly shows the relationship between a mutation, the environment, and the damage done to dopamine-containing neurons, it does not exclude other mutations and pathways from being important as well. The team plans to explore additional molecular mechanisms that demonstrate how genes and the environment interact to contribute to Parkinson's and other neurodegenerative diseases, such as Alzheimer's and ALS.

"In the future, we anticipate using the knowledge of mutations that predispose an individual to these diseases in order to predict who should avoid a particular environmental exposure. Moreover, we will be able to screen for patients who may benefit from a specific therapy that can prevent, treat, or possibly cure these diseases," Lipton said.


'/>"/>

Contact: Susan Gammon, Ph.D.
sgammon@sanfordburnham.org
858-795-5012
Sanford-Burnham Medical Research Institute
Source:Eurekalert  

Related biology news :

1. Genetics contribute to increased risk for end-stage renal disease for African Americans with CKD
2. Powerful tool for genetic engineering
3. Geneticists receive funding to improve citrus production and health
4. Researchers develop new approach to identify possible ecological effects of releasing genetically engineered insects
5. Potential drug target in sight for rare genetic disease
6. Clinical ovarian cancers display extensive genetic heterogeneity, study suggests multiple treatment
7. Genetic signature identified for RSV, the leading cause of infant hospitalizations worldwide
8. Nurture impacts nature: Experiences leave genetic mark on brain, behavior
9. Cause of genetic disorder found in dark matter of DNA
10. Genetic variation increases risk of kidney disease progression in African-Americans
11. Genetic aberration paves the way for new treatment of cancer disease
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Genetic mutation increases risk of Parkinson's disease from pesticides
(Date:2/3/2017)... , Feb. 3, 2017  Texas Biomedical Research Institute ... Larry Schlesinger as the Institute,s new President ... Biomed effective May 31, 2017. He is currently the Chair ... of the Center for Microbial Interface Biology at Ohio State ... as the new President and CEO of Texas Biomed," said ...
(Date:2/2/2017)... , Feb. 1, 2017  Central to its ... meaningful advances worldwide, The Japan Prize Foundation today ... who have pushed the envelope in their respective ... Communication. Three scientists are being recognized with the ... that not only contribute to the advancement of ...
(Date:1/26/2017)... Jan. 26, 2017  Crossmatch, a leading provider of ... solution aimed at combatting fraud, waste and abuse in ... at the Action on Disaster Relief conference in ... for UN agencies and foreign assistance organizations throughout ... and abuse are a largely unacknowledged problem in the ...
Breaking Biology News(10 mins):
(Date:2/24/2017)... 2017 China Biologic Products, Inc. (NASDAQ: CBPO) ("China ... company in China, today announced its financial results for the ... Fourth Quarter 2016 Financial Highlights Total ... in RMB terms, or increased by 13.6% in USD terms ... of 2015. Gross profit increased by 13.3% ...
(Date:2/23/2017)... -- Financial Highlights ... unaudited)Three Months Ended December 31,Twelve Months Ended December 31,20162015% ... $           300$   ... Product Revenue 3539(10)%9498(4)%Kuvan Net Product ... 756025%297303(2)%Vimizim Net Product Revenue ...
(Date:2/23/2017)... Atlanta, it seems everyone has a chance to express their ... expressive and dynamic community unlike any other. The businesses that ... With their newest salon in ... on that tradition with a unique, fresh approach to head ... the newest of 13 nationwide locations, each of them well-situated ...
(Date:2/23/2017)... ... February 23, 2017 , ... ... evaluation of multiple immunoassay-based threat detection technologies by researchers from the Pacific ... biosensor threat detection technology was found to have the best level of ...
Breaking Biology Technology: