Astrocytes reprogrammed into dopamine-forming neurons eliminate movement disorders typical of the disease in mice
Mouse astrocytes (left, colored green) can be reprogrammed into neurons (right, colored red) by treatment with antisense oligonucleotides.
© UC San Diego Health Sciences
– San Diego (USA) –
In neurodegenerative diseases, nerve cells in certain brain regions die. In animal experiments, American molecular biologists have now succeeded in replacing such cells with newly formed neurons, thereby reducing symptoms of Parkinson’s disease. To do this, the researchers blocked the production of a protein in other brain cells called astrocytes. This alone converted some of the astrocytes into functional neurons, which also connected to other neurons via extensions, the scientists report in “Nature”. In mice with an experimentally produced Parkinson’s disease, the one-time therapy increased the reduced release of the neurotransmitter dopamine in the midbrain and eliminated the movement disorders typical of the disease. Further animal experiments must now show whether the novel therapy can be used in humans without serious side effects.
“We were very surprised that we can produce so many neurons in a relatively simple way,” says Xiang-Dong Fu from the University of California San Diego. Previous attempts by other researchers to use stem cells to generate neurons and regenerate damaged brain tissue have been unsuccessful. Fu and his colleagues had accidentally discovered that connective tissue cells and other types of mouse cells develop into nerve cells when a certain gene is switched off. This gene carries the information for the production of the protein PTB, which attaches to RNA molecules and can thereby activate or inactivate genes. A strategy for the targeted elimination of PTB could be suitable to replace dead brain cells.
Mice whose dopamine-forming neurons were destroyed by special chemical treatment served as experimental animals. The dopamine deficiency caused in this way causes movement disorders, such as slowed movements, tremors and unsafe walking, which are also typical for Parkinson’s patients. The researchers initially started with cell cultures in which they grew astrocytes from mice or humans. By adding genetically modified viruses, they transferred DNA molecules into the cells, which then gave rise to RNA molecules that blocked the PTB gene. This activated several genes typical of neurons and inactivated astrocyte genes. In experiments with mice, it was subsequently possible to temporarily block the PTB gene by direct injection of so-called antisense oligonucleotides. Treatment increased the number of neurons in the midbrain by about 30 percent after twelve weeks.
The neurons produced produced dopamine and formed processes that made connections to other nerve cells. The dopamine level in the midbrain rose to normal values, so that the animals stopped showing movement disorders after three months. One treatment was sufficient for a permanent healing effect. Fu is still uncertain whether this therapeutic approach can be transferred directly to people. On the one hand, the disease triggered in the mice does not quite correspond to Parkinson’s disease. On the other hand, it has not yet been clarified whether astrocytes in older people can still be reprogrammed into neurons and how great the risk of serious side effects is. But if the new treatment strategy turns out to be suitable, the authors say, therapies for other neurodegenerative diseases such as Alzheimer’s and Huntington would also be conceivable.
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