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New Study Sheds Light on Gene-Environment Interaction in Parkinsonís
- Dec 17 2013
A new study demonstrates, at the molecular level, how an environmental trigger may transform an underlying genetic predisposition to Parkinson’s disease (PD) into the disease itself. The results appear in the December 5 issue of Cell.
The research was carried out using stem cells derived from a person with an inherited form of PD, a mutation in the alpha-synuclein gene. Stem cells have the potential to differentiate into any type of cell in the body. Recently, scientists have found ways to coax them to develop into dopamine neurons, the type of cell that is lost in PD.
Scientists led by Stuart A. Lipton, M.D., Ph.D., at the University of California at San Diego School of Medicine, carried out the research to understand how genes and the environment may together lead to Parkinson’s disease. They studied how environmental toxins, such as pesticides, could affect two types of dopamine neurons: healthy neurons and neurons with PD.
Using the stem cells that originated from the person living with PD, they created both neurons with PD (carrying alpha-synuclein mutation associated with PD) and neurons that were healthy (scientists removed the genetic mutation, in effect “curing” the neurons from PD). Next they exposed both cell cultures to low levels of pesticides and observed the effects.
- The researchers saw marked differences between the two groups of cells: in the neurons with Parkinson’s, the energy factories of the cells (called mitochondria) were less efficient than those in the healthy neurons.
- The healthy neurons were not adversely affected by low levels of pesticides.
- The scientists identified why the PD neurons were damaged – because the toxins from pesticides caused their energy factories (mitochondria) to malfunction and produce too much cellular pollution.
What Does It Mean?
This study provides insight into how an environmental trigger can interact with a genetic predisposition to PD to bring about the actual disease.
For years, scientists have asked: why do some people exposed to risk factors develop PD, while others do not? For example, of those who carry the PD mutation in the LRRK2 gene, 30 percent go on to develop Parkinson's disease, while the other 70 percent do not. Similarly, while some people exposed to high doses of pesticides that are associated with PD develop the disease, most do not.
Evidence from this study suggests that toxins in pesticides (such as those in paraquat, maneb and rotenone) may be especially harmful to cells with the alpha-synuclein PD genetic mutation. Scientists found that the toxins in pesticides interrupt a cellular pathway that helps to keeps mitochondria healthy. By identifying this pathway (called MEF2-PGC1alpha), scientists have found a new potential target for PD therapies.
Moving forward, scientists will have to replicate the study in cells with different PD-related mutations to understand whether carriers of these mutations are also more sensitive to pesticides.
Overall, this study adds to our understanding of environmental factors and PD in general. The hope is that by improving this knowledge, scientists may one day understand how to prevent or delay PD that is induced by exposures to such factors.
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Reference: Scott D. Ryan, Nima Dolatabadi, Shing Fai Chan, Xiaofei Zhang, Mohd Waseem Akhtar, James Parker, Frank Soldner, Carmen R. Sunico, Saumya Nagar, Maria Talantova, Brian Lee, Kevin Lopez, Anthony Nutter, Bing Shan, Elena Molokanova, Yaoyang Zhang, Xuemei Han, Tomohiro Nakamura, Eliezer Masliah, John R. Yates, Nobuki Nakanishi, Aleksander Y. Andreyev, Shu-ichi Okamoto, Rudolf Jaenisch, Rajesh Ambasudhan, Stuart A. Lipton, Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1a Transcription, Cell (2013), DOI: 10.1016/j.cell.2013.11.009 http://dx.doi.org/10.1016/j.cell.2013.11.009
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Source Date: Dec 17 2013