Human Stem Cells Reveal Gene-Environment Interaction in Parkinson's disease
Stuart Lipton, M.D., Ph.D.
Sanford-Burnham Medical Research Institute
NIEHS Grant P01ES016738
Researchers, supported in part by the NIEHS, used human stem cells derived from Parkinson's disease patients to show that a gene mutation combined with exposure to pesticides produces free radicals in neurons, leading to nerve cell death. Prior to this work, the link between pesticides and Parkinson's disease was based mostly on animal studies and epidemiological research.
Parkinson's disease is characterized by loss of dopamine-containing neurons in the substantia nigra, a structure located in the midbrain that plays an important role in reward, addiction, and movement. Using a patient-derived stem cell model of Parkinson’s disease, the researchers created two sets of dopamine-containing neurons that were genetically identical except for an alpha-synuclein mutation in one set of neurons. The researchers exposed the cells to pesticides, including paraquat, maneb, and rotenone. In the cells with the mutation, they observed excessive free radicals as well as damage to the dopamine-containing neurons, which led to cell death. The detrimental effects were observed even with short exposures to doses well below EPA-accepted levels.
The genetically matched neurons revealed that in the cells with the mutation, exposure to pesticides disrupts a key mitochondrial pathway that normally protects dopamine-containing neurons. Using high-throughput screening, the researchers identified a molecule called isoxazole that protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, these findings may have potential clinical implications for treating Parkinson's.
Citation: Ryan SD, Dolatabadi N, Chan SF, Zhang X, Akhtar MW, Parker J, Soldner F, Sunico CR, Nagar S, Talantova M, Lee B, Lopez K, Nutter A, Shan B, Molokanova E, Zhang Y, Han X, Nakamura T, Masliah E, Yates JR 3rd, Nakanishi N, Andreyev AY, Okamoto S, Jaenisch R, Ambasudhan R, Lipton SA. 2013. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1a transcription. Cell 155(6):1351-1364.
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