28-Jul-2006(EurekAlert) - Researchers at the Karolinska Institute in
Sweden are homing in on mechanisms that may explain one set of
causes for Parkinson's disease. In mice they have mimicked
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.
"The course of disease in these mice is strikingly similar to human
disease", says Dr. Lars Olson.

In the mouse model generated by the research team, 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, which may facilitate research aimed at finding
novel medical treatments and other therapies.

"We see that the dopamine producing nerve cells in the brain stem
slowly degenerate", says Dr. Nils-Göran Larsson. "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."

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. It has been
found that mutations in a number of genes can lead directly to
disease, while other mutations may be susceptibility factors, so
that carriers have an increased risk of becoming ill. 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", says Dr. Nils-Göran 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."

"Like in patients, the dopamine nerve cells in the new mouse model
die in a specific order", says Dr. Lars Olson. "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."