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Research focuses on Parkinson's disease genetic model

By Wai Lang Chu , 31-Jul-2006

Researchers have taken a special interest in mechanisms they have identified as an explanation for the causes of Parkinson's disease, which they say, may facilitate research aimed at finding novel medical treatments and other therapies.

The causes of Parkinson's disease have long remained a mystery. Genes and environment are both implicated, but recently there has been an increased focus on the roles of genetic factors.

True figures as to the worldwide prevalence of Parkinson's disease is sketchy but figures around 4-6m people have been mentioned.

There are over 1.5m in China alone. The disease usually has a long, subtle onset, so diagnosis occurs most often after many years of subclinical disease

Data from scientists at the Karolinska Institute used mice to mimic the disturbances of mitochondria thought to be one cause of disease.

By genetic means the disturbance of mitochondria - the energy factories of cells - were directed to those nerve cells that produce the transmitter substance dopamine and that die in Parkinson's disease.

Scientists have long suspected that genetic factors may have a greater role to play in the progression of the disease.

Previous research has established a link with mutations in a number of genes to the disease, while other mutations may be susceptibility factors, so that carriers have an increased risk of becoming ill.

In the mouse model a gene called TFAM is automatically deleted from the genome in dopamine nerve cells only. Without TFAM, mitochondria cannot function normally.

The so-called respiratory chain is compromised and energy production decreases severely in the dopamine cells.

The new mice are born healthy from healthy but genetically modified parents and will develop spontaneous disease.

Previous studies in the field have been based on researchers delivering neurotoxic substances to kill the dopamine neurons.

In the new mice, however, mice develop disease slowly in adulthood, like humans with Parkinson's disease

"We see that the dopamine producing nerve cells in the brain stem slowly degenerate," said Dr. Nils-Göran Larsson, co-collaborator of the study.

"In the microscope we can see that the mitochondria are swollen and that aggregates of a protein, probably alpha-synuclein starts to accumulate in the nerve cell bodies. Inclusions of alpha-synuclein-rich so called Lewy bodies is typical for the human disease."

A common denominator for some of the implicated genes is their suggested role for the normal functioning of mitochondria.

"Like patients, the mice can be treated with levo-Dopa, a precursor of the lost substance dopamine," said Larsson.

"The course of the disease, as well as the brain changes in this mouse are more similar to Parkinson's disease than most other models. This supports the notion that genetic risk factors are important."

Dr. Lars Olson, fellow co-collaborator of the study added that like in patients, the dopamine nerve cells in the new mouse model die in a specific order.

"We hope the mouse will help us understand why certain dopamine nerve cells are more sensitive than others, so that we can develop drugs that delay, ore even stop the nerve cell death," he added.

The study is being published this week as an Early edition in Proceedings of the National Academy of Sciences.

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