The canaries suggested a way to restore neurons
LifeSciencesToday based on URMC Materials: Scientists Coax Brain to Regenerate Cells Lost in Huntington's Disease
Scientists have managed to activate brain stem cells and achieve the formation of neurons that die in Huntington's disease. In an article published in the journal Cell Stem Cell (Benraiss et al., Sustained Mobilization of Endogenous Neural Progenitors Delays Disease Progression in a Transgenic Model of Huntington's Disease), they describe the trigger of neurogenesis in mice with a model of this disease and convincingly prove the successful integration of new cells into existing neural networks of the brain, dramatically increasing life expectancy of sick animals.
"This study demonstrates the feasibility of a completely new concept for the treatment of Huntington's disease – the use of endogenous neural brain stem cells to regenerate cells lost as a result of the disease," says Steve Goldman, MD, PhD, co–director of the Center for Translational Neuromedicine, a neurologist at the University of Rochester Medical Center (URMC). (Center for Translational Neuromedicine).
Huntington's disease is a hereditary neurodegenerative disease characterized by the loss of a specific type of cells – medial spiny neurons – that play an important role in the coordination of movements. Symptoms of Huntington's disease are involuntary movements, impaired coordination and, ultimately, cognitive decline and depression. There are no ways to slow down the development of the disease, which affects about 30 thousand people in the United States alone, today.
The idea of Dr. Steve Goldman's new strategy is the result of his many years of research on the plasticity of canary neurons. Songbirds, such as canaries, have interested biologists with their ability – unique in the animal world – to form new brain neurons in adulthood. This process, called neurogenesis, was discovered by Goldman and Fernando Nottebohm from Rockefeller University in the early 80s, when scientists realized that the process of learning new songs was accompanied by the formation of new neurons in the area of the bird brain responsible for controlling singing.
"The information we needed to understand how to achieve the formation of new neurons in the adult brain tissue was essentially given to us by our work with canaries," says Dr. Goldman. "As soon as we understood how this happens in birds, we started reproducing this process in the adult mammalian brain."
The human body, in principle, has the ability to form new neurons. In the 1990s, Goldman's laboratory demonstrated that there is a source of neural progenitor cells in the lining of the ventricles–structures in the center of the human brain. At an early stage of development, these cells actively produce neurons. However, soon after birth, neural stem cells stop the formation of both neurons and glial cells. Some areas of the human brain, the most striking example of which is the hippocampus responsible for memory, continue to produce neurons in adulthood. But in the striatum, destroyed by Huntington's disease, this ability is "turned off" in adulthood.
Over the past decade, Dr. Goldman and his group have been trying to decipher the precise chemical signaling mediating the formation of neurons and glial cells by neural stem cells. One of the most important keys was obtained in studies on canaries. In the area of their brain responsible for learning new songs and forming new neurons, scientists observed regulated expression of a protein called brain derived neurotrophic factor (BDNF). The synthesis of this protein is the trigger for the formation of neurons by local neural stem cells.
In addition, scientists realized that it was necessary to simultaneously suppress the formation of glia by neural stem cells. They found that the combination of BDNF with the noggin protein, which inhibits the chemical pathway that controls the formation of glial cells, makes it possible to successfully switch the molecular mechanisms of stem cells to the formation of neurons only.
The next challenge was the precise and stable delivery of these two proteins – BDNF and noggin–to the brain region involved in Huntington's disease. In order to transmit the necessary molecular instructions to neural stem cells, they, in collaboration with scientists from the University of Iowa, modified an adeno-associated virus used as a vector in gene therapy.
This virus infected target cells in the brains of mice with Huntington's disease and allowed for sustained overexpression of both BDNF and noggin. This, in turn, activated neighboring neural stem cells, which began to form medial spiked motor neurons. Continuously forming new neurons migrated to the striatum, where they then integrated into existing neural networks.
Scientists have managed to significantly increase the survival rate of mice, and in some cases their life expectancy has doubled. In addition, they developed a way to label new neurons and observed that the cells formed fibers that connected them to distant targets, thereby providing electrical communication.
Medial spiny neurons (green),
integrating into existing neural networks
(photo: University of Rochester Medical Center)
After establishing the possibility of the formation of new replacement neurons in mouse models of Huntington's disease, scientists reproduced this result on the brains of healthy squirrel monkeys – a step that significantly brings this study closer to clinical trials.
"Stable delivery of BDNF and noggin to the adult brain is clearly associated with both increased neurogenesis and slowing the progression of the disease," Dr. Goldman sums up. "We believe that our data suggest the possibility of using this process as a viable therapeutic strategy for the treatment of Huntington's disease."
Portal "Eternal youth" http://vechnayamolodost.ru10.06.2013