Scientists search for Parkinsons genes in Tasmania

Within a day of putting out a call for families with a history of Parkinson's disease to participate in a project to identify susceptibility genes for the disease, Hobart's Menzies Research Institute had five families signed up.

The response confirmed for Parkinsons expert Prof Malcolm Horne, of Melbourne's Florey Research Institute, that Tasmania was the ideal location for a pilot study that will eventually expand into a major, Australia-wide research project.

The Florey and the Menzies are partners in the project, which is recruiting families in which at least three immediate relatives -siblings, or members of successive generations - have developed the debilitating tremors of Parkinson's diseases.

The proximate cause of Parkinson's disease is severe decline in production of the neurotransmitter dopamine in the brain, due to the death of dopaminergic neurons in a region called the substantia nigra.

Professor Horne has made major contributions to understanding the mechanisms by which a misfolded protein, alpha-synuclein, aggregates in dopaminergic neurons, forming distinctive spots called Lewy bodies. Lewy bodies spawn oxygen free radicals that poison and eventually kill dopaminergic neurons.

But Horne said mutations in the alpha-synuclein gene that cause misfolding and aggregation of its protein, or impair the mechanisms that would normally degrade and clear the toxic protein from the brain, account for less than 10 per cent of the genetic risk of developing Parkinson's.

That leaves at 90 per cent of the genetic risk unaccounted for. Horne expects that other, as-yet anonymous susceptibility genes, will be involved in some way in the breakdown and clearance process mediated by liver enzymes, or excessive production of dopamine in the brain.

Menzies Institute epidemiologist Ass Prof Alison Venn, is coordinating the recruitment phase, and will also work to identify environmental factors that may interact with susceptibility genes to cause Parkinson's disease

Parkinson's disease is predominantly a disorder of aging. More than 100,000 Australians, most over the age of 40, have already been diagnosed with the disorder.

Venn said that with Australia's aging population, more and more people will develop the disease. The 'greying' of Tasmania's population is particularly rapid due to the combination of falling birth rates and low immigration rates.

Venn said the study has two objectives: to help define the contribution of known susceptibility genes for Parkinson's, and to identify new ones.

Horne described Tasmania as Australia's equivalent of Iceland, which, with its small founding population and long history of genetic isolation, is providing a bonanza for geneticists investigating hereditary disorders.

While Tasmania does not have Iceland's long history of genetic isolation, its population is a similar size, and descends from a relatively small number of free colonists and convicts, resulting in a legacy of strong "founder effects" for hereditary disorders including epilepsy, glaucoma and Parkinson's disease.

"The first task is to get the DNA samples in the bank, and accurately phenotype the population," he said. "We can do that relatively easily because the population is fairly small, and we can see pretty much every member of the families with a history of Parkinson's."

Researchers are also using data from the Health Insurance Commission to identify Parkinson's patients, through prescriptions written in Tasmania for the drug L-dopa, which used almost exclusively to treat the disorder.

"Another very important reason for choosing Tasmania is that it has kept very detailed records of births, deaths and marriages since it was settled, so it's much easier to do genealogy studies than in states like Victoria or NSW," Horne said.

The Florey Institute will perform the DNA analyses itself, using its own powerful computers to screen for genetic markers that appear more frequently in Parkinson's patients than in their unaffected first-degree relatives.

The Florey and Menzies institutes have applied for an NHMRC grant to fund the study, but Horne said they have already secured around $100,000 in donations from philanthropic trusts to begin the pilot study.