Charité scientists decipher mechanism to prevent programmed cell death of nerve cells
Oxygen and glucose are the food of our brain. If they are absent, such as during a stroke, nerve cells die. An international research team at Charité – Universitätsmedizin Berlin, Germany, and McMaster University, Canada, has discovered a novel mechanism to prevent this cell death. The results of the study have now been published in the journal Proceedings of the National Academy of Sciences of the USA.
Brief periods of oxygen deprivation can act like a training session for cells in the human body. As a result, they are better able to survive longer periods of oxygen deprivation – they are “prepared”, so to speak. In addition, it is known that oxygen deficiency also affects sugar metabolism. However, sugar metabolism and programmed death of a cell so far have been regarded as independent events. A research team led by the two scientists Philipp Mergenthaler and Andreas Meisel, who work together at the NeuroCure Cluster of Excellence at the Charité, now explains the link between these two processes. The survival of the cell is regulated by a key enzyme of sugar metabolism, the so-called hexokinase II. This enzyme alters the sugar nutrient glucose in such a way that it can be processed by the cell. The researchers discovered that this enzyme is activated in the nerve cells of the brain after a lack of oxygen. This happens, for example in the case of a stroke, a circulatory disorder of the brain, resulting in insufficient oxygen and nutrient supplies in the brain. The enzyme then plays a protective role. "This self-protection of the nerve cell represents an important basis for further research, from which it may be possible to develop optimized stroke therapies," says Meisel.
However, the molecular mechanisms of the oxygen deficiency and altered cellular metabolism not only play a role for stroke, but are also very important for tumor development and the defense against infections by the immune system. Consequently, the enzyme is held responsible for alterations in sugar metabolism of malignant tumors. However, if there is glucose deficiency in the cell and normal oxygen supplies, it can also cause cell death. "Understanding the basic mechanism of how sugar metabolism regulates cell death might thus be used to protect against stroke, but could also be used to selectively cause cell death in malignant tumors," Mergenthaler explains. The mechanism how sugar metabolism regulates cell death thus fundamentally expands the basic medical knowledge of many diseases.
Originalpublikation: Mergenthaler P, Kahl A, Kamitz A, van Laak V, Stohlmann K, Thomsen S, Klawitter H, Przesdzing I, Neeb L, Freyer D, Priller J, Collins TJ, Megow D, Dirnagl U, Andrews DW, Meisel A. Mitochondrial Hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state. Proc Natl Acad Sci U S A. 2012; published ahead of print January 10,2012. doi: 10.1073/pnas.1108225109
NeuroCure is a Cluster of Excellence in the framework of the Excellence Initiative funded by the German federal and state governments since 2007. The interdisciplinary research alliance crosslinks basic neuroscience research and clinical application to translate scientific findings on the functioning of the nervous system and neurological diseases to effective therapies.
Dr. Philipp Mergenthaler
Charité – Universitätsmedizin Berlin
NeuroCure Clinical Research Center
t: +49 30 450 560 020
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