Chemical trigger of Parkinson's found

By Mike Nagle

- Last updated on GMT

Related tags Dopamine

A group of scientists believe they have cracked the riddle of how
Parkinson's disease is triggered - a breakthrough that could lead
to more effective therapies against the disease.

Parkinson's disease occurs when a protein called alpha-synuclein (AS) clumps together in the substantia nigra part of the brain (these clumps are often also called Lewy bodies).

This causes dopamine-producing nerve cells to stop working or die, which in turn triggers the debilitating effects of the disease.

What scientists didn't know was why AS proteins come together in the first place.

Until now that is.

Prof. William Burke and his team at the Saint Louis University School of Medicine think they have found the answer and it turns out that dopamine itself plays a role in destroying the cells that produce it, through a by-product called 3,4-dihydroxyphenylacetaldehyde (DOPAL).

"This is very exciting," he said.

"This is the first time that anyone has ever established that it is a naturally occurring by-product of dopamine that causes alpha-synuclein to aggregate, or clump together.

It's actually DOPAL that kicks this whole process off and results in Parkinson's disease."

Though it may seem strange that dopamine helps destroy the cells that produce it, its role has previously been suggested.

Given that AS is present all over the brain, scientists have been puzzling over why it only congregates in certain areas.

As Nathan Pankratz and Tatiana Foroud from the Indiana University School of Medicine wrote in their paper 'Genetics of Parkinson Disease' ( NeuroRx journal), one obvious difference between the cells in the substantia nigra and those in other parts of the brain, is the presence of dopamine.

DOPAL was predicted to be toxic some 50 years ago, but it wasn't until Burke and his colleagues synthesised the molecule, that this hypothesis could be tested.

Since then, the St Louis University team, joined by others from Washington University in St. Louis, have been working to find out what effects DOPAL has in the brain.

The team tested DOPAL-induced AS aggregation in a cell-free system, in vitro in dopamine neuron cultures and in vivo with injections into the brains of rats, by Western blots, fluorescent confocal microscopy and immunohistochemistry.

They found that at physiologically relevant concentrations, DOPAL causes AS to aggregate in the cell-free system and in cell cultures.

In the rats, injection of DOPAL caused dopamine neurons to die and AS clumps to form.

The research is published in an online edition of Acta Neuropathologica .

According to the UK Parkinson's Disease Society, there are around four million people who suffer from the disease.

Currently, the loss of dopamine that characterises the disease is normally counteracted through treatment with either dopamine activators or administration of the dopamine precursor levodopa (L-dopa).

However, this latter drug becomes less effective over time and the increasing doses needed cause side effects such as uncontrollable movement.

According to Burke, this new research could lead the way to neuroprotective therapies - those that actually prevent the nerve cells from dying off in the first place.

"We believe this work represents a very significant breakthrough in understanding the complicated chemical process that results in Parkinson's disease," he added.

Related topics Preclinical Research

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