Genetics and pesticide exposure 'double hit' might underlie Parkinson's for some

People with a particular genetic mutation may face greater risks of developing Parkinson's disease if exposed to certain pesticides, according to scientists.

The study, published in Cell, shows the biological processes underlying the death of nerve cells containing dopamine. Dopamine is a neurotransmitter — a chemical signal — essential for movement and coordination. Destruction of dopamine-containing neurons may lead to Parkinson's disease.

Pesticides can damage neurons by producing highly chemically reactive molecules known as free radicals. Neurons containing a specific genetic mutation are more susceptible to damage from free radicals.

'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 Professor Stuart Lipton, senior author of the study and director of Sanford-Burnham Medical Research Institute's Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research.

The mutation affects a gene encoding the alpha-synuclein protein. Alpha-synuclein is the main component of the protein clumps found in the brains of people with Parkinson's disease. When bombarded by toxins — for example, if exposed to pesticides — the protein MEF2C is inhibited in neurons containing the mutation.

MEF2C is a transcription factor — a protein that binds to DNA sequences, controlling whether genes are transcribed into proteins themselves. Normally, MEF2C stimulates the production of a protein that helps protect the neuron, but disruption of this pathway leads to an early death for the cell.

'We observed the detrimental effects of these pesticides with short exposures to doses well below [US Environmental Protection Agency]-accepted levels', said lead author Dr Scott Ryan, a researcher in the Del E. Webb Center.

To investigate how the genetic mutation disrupts the biological pathway, researchers created induced pluripotent stem (iPS) cells from the skin of people with Parkinson's disease. These skin cells contained a mutation in the SNCA gene, which encodes alpha-synuclein.

The team  corrected the genetic mutation in one set of iPS cells before turning them into dopamine-containing neurons. As well as studying the two sets of iPS cells — one holding the mutation and the other with the mutation 'knocked out' — the team also 'knocked in' the same mutation in a separate line of embryonic stem cells.

After mapping the biological pathway, the group was able 'to identify molecules that could inhibit the effect of free radicals on the pathway', according to Professor 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'.

The researchers cautioned that although their study identified a clear relationship between genetic and environmental factors, they could not rule out the potential importance of other mutations and biological pathways.