Patient-derived stem cells reveal how an alpha-synuclein mutation increases vulnerability to pesticides and contributes to Parkinson’s disease
Researchers identify a protective molecule and clarify a gene–environment mechanism that kills dopamine-producing neurons.
A multi-institutional research team has provided new molecular insight into how genetic susceptibility combined with environmental exposure can destroy the dopamine-producing neurons that control movement. Published in Cell, the study demonstrates that a specific mutation in the alpha-synuclein gene makes human neurons far more vulnerable to commonly studied pesticides, and it identifies a compound that can protect these neurons from pesticide-induced damage.
The team, led by Stuart Lipton, M.D., Ph.D., director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research at Sanford-Burnham Medical Research Institute, together with collaborators Rajesh Ambasudhan, Ph.D., and Rudolf Jaenisch, M.D., used patient-derived cells to model Parkinson’s disease in the laboratory. They started with skin cells from patients carrying a mutation in the gene that encodes alpha-synuclein, the protein that aggregates into Lewy bodies—hallmarks of Parkinson’s pathology.
Researchers converted those skin cells into human induced pluripotent stem cells (hiPSCs) containing the mutation, and in parallel generated isogenic control cells in which the mutation was corrected. Both mutant and corrected hiPSCs were differentiated into A9 subtype dopamine neurons—the specific neurons most affected in Parkinson’s disease—producing two genetically matched neuronal populations that differed only by the single alpha-synuclein mutation.
When exposed to pesticides such as paraquat, maneb, and rotenone, neurons carrying the alpha-synuclein mutation produced excessive reactive oxygen and nitrogen species (free radicals), according to co-author Frank Soldner, M.D. These free radicals damaged cellular machinery and led to selective degeneration of dopamine-producing neurons. Scott Ryan, Ph.D., the paper’s lead author, emphasized that the harmful effects were detectable after short exposures at concentrations below levels commonly accepted by regulatory agencies.
By comparing genetically matched neurons that differed only by the mutation, the researchers were able to pinpoint the molecular pathway targeted by the pesticide-induced oxidative stress. Free radicals impaired a mitochondrial transcriptional pathway governed by MEF2C and PGC1alpha, a pathway known to support mitochondrial function and neuronal survival in dopamine neurons. Damage to MEF2C diminished the protective activity of this pathway, making mutant neurons unable to withstand the additional stress imposed by pesticides.
Armed with this mechanistic understanding, the team performed high-throughput screening to find compounds that could interrupt the damaging chain of events. They identified isoxazole as a molecule that restored function in the MEF2C-PGC1alpha pathway and protected mutant dopamine neurons from pesticide-triggered cell death. Lipton noted that derivatives of isoxazole appear in several FDA-approved drugs, raising the possibility of drug repurposing strategies that might translate more rapidly into clinical testing.
The study establishes a clear example of gene–environment interaction in Parkinson’s disease but does not claim exclusivity for this particular mutation or pathway. Other genetic variants and molecular mechanisms likely also contribute to disease risk. The research team plans to extend this patient-derived stem cell approach to identify additional gene–environment interactions and molecular targets relevant to Parkinson’s and other neurodegenerative disorders such as Alzheimer’s disease and ALS.
Looking ahead, Lipton and colleagues suggest two practical applications of these findings: first, to use knowledge of specific genetic vulnerabilities to advise individuals about environmental exposures they should avoid; and second, to match patients with targeted therapies—potentially preventing or slowing neurodegeneration in those at greatest risk.
Notes on funding and publications
Funding for this research included NIH grants P01 HD29587, P01 ES016738, and P30 NS076411 (to S.A.L.), R37 CA084198 (to R.J.), a UMDF grant (to R.A.), and a Parkinson Society of Canada Fellowship (S.D.R).
Contact: Susan Gammon, Ph.D., Sanford-Burnham Medical Research Institute
Source: Sanford-Burnham Medical Research Institute press release
Image credit: Sanford-Burnham Medical Research Institute (adapted from the press release)
Original research article: “Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription,” DOI: 10.1016/j.cell.2013.11.009. Authors include 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, and Stuart A. Lipton. Published online November 27, 2013.
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