We’ve just published new work in Chemical Science about how the chemistry of two essential ingredients of our brain stew may be at the very heart of Parkinson’s disease pathology.
Iron and dopamine are both necessary for healthy brain function, but are highly reactive when they come in close chemical proximity. Iron is present in every cell in the brain, yet dopamine is usually confined to a select few types of neurons, where it acts as the primary neurotransmitter in a number of systems, including movement, reward and learning. In Parkinson’s disease, neurons producing dopamine in the nigrostriatal, or motor pathway, degenerate, whilst the adjacent neurons of the mesolimbic (thought to be the ‘reward’ pathway) do not. We found that the region of the brain damaged in Parkinson’s disease naturally has a high iron and dopamine content, and that this balance can reach a ‘tipping point’ when we apply a toxin mimicking Parkinson’s.
In this paper, we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS; see this short video from one of the best in the business, Detlef Günther’s lab) to create maps of iron in the brain of mice, and looked at where iron colocalised with the dopamine-producing enzyme tyrosine hydroxylase, which was labeled with a gold nanoparticle:
By using a laser beam with a 5 micrometer diameter, we were able to distinguish individual neurons in sections of mice brain and directly measure the iron present:
From this, we were able to assign a numerical value quantifying the relationship between iron and dopamine in cells considered ‘at-risk’ in Parkinson’s disease. The substantia nigra pars compacta, which is the area showing the most marked damage in Parkinson’s brains, has a naturally higher ‘index’ of iron and dopamine than any other region in the brain. When we exposed mice to 6-hydroxydopamine, a toxic byproduct of the breakdown of dopamine (which is thought to be a possible contributor to cell death in Parkinson’s disease) to one side of the brain, this index shifts even higher when compared to unlesioned side (panel G in the figure below).
So what does this mean? Around 90% of Parkinson’s disease cases are called ‘idiopathic’, in that we don’t know what causes it. To develop new treatments for Parkinson’s disease, we need to know what goes wrong in the first place, before cells start dying, at the molecular level. This method provides a direct measure of how iron and dopamine interact to cause Parkinson’s disease, which we can now use to test the effectiveness of drugs that target iron in preventing cell death.
Check out this story at the Royal Society of Chemistry’s Chemistry World website.