Last updated: 15 October 2014 at 2am PST
Parkinson's Disease is the second most common
neurodegenerative disorder. In Germany alone, almost half a million people are
affected. The focus of the disease is the progressive degeneration of
dopamine-producing nerve cells in a certain region of the midbrain, the
substantia nigra. Misfolded proteins are the cause. Until recently, it was
unclear why damage is confined to specific nerve cells. A team or researchers
led by Frankfurt neurophysiologists has now defined how this selective disease
process begins using a genetic mouse model of Parkinson's disease.
The progressive death of a certain type of
nerve cells - dopaminergeic neurons - in the substantia nigra causes dopamine
deficiency, which is the major cause for the motor deficits in Parkinson
patients. Although it is possible to therapeutically compensate the dopamine
deficiency for a certain period of time, by e.g. administration of L-dopa or
dopamine gonists, these therapies do not stop the progressive death of neurons.
In the last two decades, researchers have
identivied gene mutations and toxic protein aggregates to cause
neurodegeneration, with protein a-synuclein having an essential role. Until
recently, it was unclear why only specific types of nerve cells, such as
dopaninergic neurons in the substantia nigra, are affected by this process,
while others, also expressing the mutant a-syncuclein such as dopaminergic
neurons in the immediate vicinity, survive the disease process with little
damage.
The research group led by Dr Mahalakshmi
Subramaniam and Prof. Jochen Roeper at the Institute for Neurophysiology at the
Goethe University, in collaboration with researchers from Frankfurt's
Experimental Neurology Group and from Freiburg University, demonstrated for the
first time how sensitive dopaminergic substantia nigra neurons functionally
respond to toxic proteins in a genetic mouse model. A mutated a-synculein gene
(A53T), which causes Parkinson's Disease in humans, is expressed in the mouse
model.
In the current issue of the Journal of
Neuroscience, the researchers report that the sensitive dopaminergic
substantia nigra neurons respond to the accumulation of toxic protein by
significantly increasing the electric activity in the affected mid brain
regions. In contrast, the less sensitive, neighboring dopaminergic neurons were
not affected in their activity. "This process begins as early as one year
before the first deficits appear in the dopamine system, and as such it
presents an early functional biomarker that may have future potential for
preclinical detection of impending Parkinson's Disease in humans,"
explains Prof Jochen Roeper. "The potential for early preclinical
detection of subjects at risk is essential for the development of
neuroprotective therapies."
The Frankfurt group, also identified a
regulatory protein, an ion channel, which causes the increase in electric
activity and the associated stress in nerve cells in response to oxidative damage. This
channel provides a direct new target protein for the neuroprotection of
dopaminergic neurons. In brain slices, the dysfunction of this ion channel
acting as an "electric brake" for dopamine neurons was reversible
just by adding redox buffers. If therapeutic drugs could reduce the channel's
redox sensitivity in future mouse models, the death of dopaminergic neurons in
the substantia nigra might be prevented. Currently, the researchers are
studying whether similar processes occur with other Parkinson genes and in
aging itself. "The long-term objective is to investigate the extent to
which these results from mice might be transferred to humans," says
Roeper.
http://www.medicalnewstoday.com/releases/283893.php
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