FRANKFURT. Parkinson’s disease is the second most common neurodegenerative disease. In Germany alone, nearly half a million people are affected. In the center of this disease is the progressive death of nerve cells in a specific region of the midbrain, the substantia nigra. At fault are misfolded proteins. But why this damage only certain nerve cells, was previously unknown. A research team led Frankfurter neurophysiologists has now elucidated the beginning of the disease process in the mouse model.
By the progressive death of a certain type of nerve cells, the dopaminergic neurons in the substantia nigra, creating a dopamine deficiency, which manifests itself by shaking palsy. Although the defect can be compensated therapeutic for some time, for example, by administration of L-dopa or dopamine agonists, but the increasing demise of neurons is characterized unstoppable.
The cause of the neurodegeneration researchers were able to identify toxic protein aggregates in the last two decades, with the protein a-synuclein plays a key role. It was not clear exactly why only very specific groups of nerve cells – such as the dopaminergic substantia nigra neurons – are affected by this process, while others, for example immediately adjacent dopaminergic neurons, this disease process through almost unscathed.
The research team led by Dr. Mahalakshmi Subramaniam and Prof. Jochen Roeper from the Institute of Neurophysiology at Goethe University was able to show in collaboration with colleagues in Frankfurt from the Experimental Neurology and researchers at the University of Freiburg for the first time using a genetic mouse model, such as the sensitive dopaminergic neurons of the substantia nigra respond to the toxic proteins. In the mouse model, a mutant a-synculein gene (A53T) is expressed, which also causes Parkinson’s in humans.
As the researchers report in the current issue of the Journal of Neuroscience, react sensitive dopaminergic neurons of the substantia nigra in an accumulation of toxic proteins by increasing their electrical activity in the intact brain significantly. In contrast, the less sensitive neighboring dopaminergic neurons remain unaffected. “This process began in the mouse a year before the first deficits of the dopamine system and is thus a first functional biomarkers that could possibly help in future also in humans for early detection of incipient Parkinson’s disease,” explains Prof. Jochen Roeper. “For the development of neuroprotective therapies, the possibility of preclinical screening of persons at risk is essential.”
Frankfurter researchers also have the protein switch – an ion channel – identified, the oxidative disorder for increasing the electrical activity and the associated stress in the nerve cells is responsible. So they have found a new target protein for neuroprotection of dopaminergic neurons. In brain slices can be the fault of the “electric brake” in the ion channels already through the gift of Redoxpuffern undone. If it is possible in the future to reduce its sensitivity in the mouse model by drugs, the death of dopaminergic neurons in the substantia nigra could be prevented. The researchers are currently investigating whether similar processes can also set other Parkinson’s genes and in aging. “Long term objective is then to check to what extent the results can be transferred from the mouse to humans,” said Roeper.
Publication: Mahalakshmi Subramaniam et al .: mutant a-synuclein Enhances Firing Frequencies Dopamine in substantia nigra neurons by Oxidative Impairment of A-Type Potassium Channels, The Journal of Neuroscience, October 8, 2014 • 34 (41): 13586 -13599. doi: 10.1523 / JNEUROSCI.5069-13.2014.
Information: Prof. Jochen Roeper, Institute of Physiology, University Hospital Frankfurt, Tel .: (069) 6301-84091, firstname.lastname@example.org.