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.