A research group from Trinity College has discovered new facts about Parkinson's disease. Eoin Burke-Kennedy reports
Research by a team of scientists in Trinity College Dublin has shed new light on the process of cell death in Parkinson's disease.
The Department of Biochemistry's Neurodegeneration Group has discovered that a typical brain cell will begin to die if the mitochondria - the energy-producing part of the cell - is inhibited by 70 per cent.
But the mitochondria inside dopamine brain cells - which are associated with Parkinson's disease - were found to be significantly weaker and more susceptible to damage from toxins and other agents.
Head of the group Dr Gavin Davey says: "The majority of mitochondria in the brain have a 70 per cent reserve activity or energy threshold, but the ones inside dopamine neurons seem to be lower."
Davey believes "mitochondrial dysfunction" lies at the heart of Parkinson's disease.
The disorder arises from an accelerated loss of dopamine-producing brain cells which are central to muscle control.
The average person loses around 10 per cent of their dopamine neurons every decade but in Parkinson's patients, they die at a faster rate.
The disease manifests itself in the form of decreased movement, muscular rigidity and tremors when about 80 per cent of the dopamine neurons are gone.
"If we lived long enough, most of us would get Parkinson's," says Davey, "because these cells are dying naturally with age".
The most significant breakthrough in understanding the disease came in the early 1980s in rather tragic circumstances.
A group of young drug users in San José, California suddenly developed symptoms similar to late onset Parkinson's disease.
They had been experimenting with a synthetic heroin that was found to have been contaminated with a chemical compound called MPTP which, when injected intravenously, selectively wiped out dopamine neurons.
At first, doctors thought the patients suffered from a severe form of schizophrenia, but following a course of treatment with the anti-Parkinson's drug L-dopa they showed a dramatic improvement.
Unfortunately, the side effects associated with L-dopa occurred more rapidly in the drug users than in patients with classic Parkinson's disease and their recovery was limited.
"MPTP provided us with a model of how dopamine neurons in Parkinson's disease may die," says Davey.
Although MPTP is not present in our natural environment and therefore cannot explain the occurrence of normal Parkinson's disease, Davey says its discovery has fuelled belief that the disease may be in part due to exposure to some toxic agent in the environment.
Scientists have for some time noted that the incidence of Parkinson's disease on the South Pacific island of Guam is 50 times greater than in the rest of world.
A recent study blamed the use of flour from the highly toxic seed of the cycad plant.
There is a vast array of epidemiological evidence relating Parkinson's disease to environmental agents but little in the way of a definite cause.
It is known there is a higher rate of the disease in the industrialised world, which some experts have linked to the presence of industrial pollutants.
A prolonged exposure to certain pesticides has been found to result in a Parkinsonian-type syndrome.
Research has also revealed that people who drink well water are more likely to contract the disease.
To further complicate matters, there is a reduced incidence of the disease in smokers and in people who drink coffee.
One theory suggests a chemical in cigarette smoke and coffee may be protecting brain cells in some way.
But Davey says despite these epidemiological clues, we have yet to find a toxin in the environment which explains the sporadic incidence of Parkinson's disease worldwide.
One major difficulty in pinpointing a cause, says Davey, is that postmortem examinations do not reveal what caused the cells to die.
"The area of the brain that is damaged shows there is nothing left - so you don't know if a toxin was the cause originally as all you see is a reduction in cell numbers," he says.
"One theory is that maybe a virus earlier in the patient's life, maybe in adolescence, wipes out a significant portion of dopamine cells. This would only become a problem when the patient's natural rate of cell death reduces the dopamine cell count to below 20 per cent resulting in Parkinson's disease."
But Davey believes the cause of the disease may be multi-factorial. He cites another possible reason for the death of dopamine cells in the brain known as oxidative stress.
When the mitochondria use oxygen to produce energy some of the oxygen molecules become unstable, forming free radicals.
In a process known as oxidation, the free radicals attempt to attach themselves to neighbouring molecules especially in the presence of metals such as iron.
The process - which is part of the natural ageing process in humans - is known to damage tissue, including brain cells.
Postmortems on people with Parkinson's have found increased levels of iron in the brain, especially in the area where dopamine neurons are situated, suggesting excessive oxidative damage.
This ties in with the theory that Parkinson's disease may be an accelerated ageing process.
Although the majority of Parkinson's disease cases are not thought to have a genetic component, up to 10 per cent of sufferers are believed to inherit the disorder.
This can be traced to a number of gene mutations including one for the protein alpha-synuclein.
A mutated form of this protein has been found in small deposits called lewy bodies in the brain cells in patients with a family history of the disease and excessive accumulation of the normal form of this protein is found in sporadic sufferers.
It is not clear what role these proteins play in the disease, says Davey, but we know they are associated with the function of mitochondria.
Davey believes the mytochondria in dopamine cells may have a different complement of proteins to other mytochondria and because they are lacking in certain proteins they may be more susceptible to damage.
"The protein theory comes from a different direction than the toxin theory but it ties in with the mitochondrial dysfunction model of Parkinson's disease.
"If we remedy the mitochondrial dysfunction, we can stop the neurons from dying," he says.
"We have lots of animal models which prevent mitochondrial damage and prevent cell death but at the moment nothing that works in humans."