Rapamycin against neurodegenerative diseases
By suppressing protein synthesis, rapamycin saves energy and slows down neurodegeneration
LifeSciencesToday by Salk Institute for Biological Studies: Tamping down neurons’ energy use could treat neurodegeneration
According to data obtained by scientists from the Salk Institute for Biological Research, an FDA-approved drug improves the condition of brain cells by reducing their energy costs. This drug, rapamycin, increases the lifespan of damaged neurons, forcing them to reduce protein synthesis and thereby save energy.
Rapamycin is already known as a drug that increases life expectancy, softens the symptoms of many diseases and, at the cellular level, slows down the rate of protein synthesis. But a new study by scientists from the Salk Institute, published in the journal eLife (Zheng et al. The allowance of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration) shows that rapamycin can also affect the degree of damage to nerve cells associated with Ley syndrome, a rare genetic disease, and possibly with other neurodegenerative diseases.
"Our study shows that one of the most significant amounts of energy is spent on protein synthesis in neurons and that neurons in Ley syndrome degenerate because they cannot maintain a sufficiently high level of energy," says the head of the study, Professor Tony Hunter.
Previous studies have shown that rapamycin, which blocks a key cellular energy sensor, affects the immune system, increases life expectancy and treats diseases, including lupus and Alzheimer's disease. The researchers assumed that this drug prevents neurodegeneration in Alzheimer's disease by stimulating the destruction of damaged components and aggregated proteins. But recent data suggested the possibility that this drug has an effect on mitochondria – organelles that produce energy in the form of adenosine triphosphate.
A researcher in the laboratory of Professor Hunter Xinde Zheng, PhD, has already studied the properties of cells in Ley syndrome, in which inherited neurodegeneration is caused by a mutation in mitochondrial DNA that reduces ATP production. Dr. Zheng wanted to find out how rapamycin affects neurons with mitochondria carrying this mutation. He and Hunter joined forces with Professor Rusty Gage's genetics laboratory. Zheng and Leah Boyer, then a researcher at Gage's laboratory and now director of Stem Cell Core, obtained damaged neurons by reprogramming skin cells of patients with Ley syndrome first into stem cells and then into neurons.
Although, in order to live, cells must synthesize proteins, this process is extremely energy-consuming, and, in diseased cells, leaves too few energy resources to withstand stress and other needs.
"Reducing protein synthesis in aging neurons allows the cell to direct more energy to their proper clotting and to fight stress," explains Dr. Zheng. "The significance of our discovery is that modulating protein synthesis may become a common approach to the treatment of neurodegeneration."
The researchers found that in the Petri dish, neurons with the mitochondrial mutation of Ley syndrome degenerated and showed clear signs of a lack of energy, while the same cells exposed to rapamycin synthesized more ATP, and their degradation was less pronounced. With reduced protein synthesis, diseased and damaged neurons lived longer.
"We are surprised and pleased that the property of rapamycin to reduce protein synthesis as a mode of energy austerity may lead to the emergence of a method for the treatment of mitochondrial-related neurodegenerative diseases," Professor Gage comments on these results.
According to Professor Hunter, their study is a good example of the value of studying diseases in a Petri dish.
"This has led to many new ideas about the biology underlying this rare and little–studied disease," the scientist notes.
To find out whether the results of this study are correct in relation to model animals with Ley syndrome and other neurodegenerative diseases, it is necessary to conduct additional experiments. In addition, it is necessary to establish exactly how rapamycin changes cellular metabolism.
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12.05.2016