Newswise — Just as humans undergo daily stress, so do our individual cells. The cellular variety, called oxidative stress, is caused by the build-up of free radicals, which over time inflict damage linked to aging and age related diseases such as Alzheimer's. Researchers at Harvard Medical School (HMS) have now defined a molecular signaling pathway by which oxidative stress triggers cell death, a finding that could pave the way for new drug targets and diagnostic strategies for age-related diseases. The findings are reported in the June 2 issue of Cell.
"A common molecular denominator in aging and many age-related diseases is oxidative stress," says the study's lead author Azad Bonni, MD, PhD, HMS associate professor of pathology. The skin of a bitten apple will brown because of its exposure to air, and in some ways that is a good metaphor for the damage that oxidative stress is causing to neurons and other types of cells over time.
Humans and other organisms depend on oxygen to produce the energy required for cells to carry out their normal functions. A cell's engine, the mitochondria, converts oxygen into energy. But this process also leaves a kind of exhaust product known as free radicals. When free radicals are not destroyed by antioxidants, they create oxidative stress. As the body ages, it produces more and more free radicals and its own antioxidants are unable to fight this process, which results in the generation of highly reactive oxygen molecules that inflict cellular damage by reacting with biomolecules including DNA, proteins, and lipids. A lifetime of oxidative stress leads to general cellular deterioration associated with aging and degenerative diseases.
How the oxidative-stress signals trigger these profound effects in cells has remained unclear. But Bonni and his research team, including Maria Lehtinen, a graduate student in the HMS program in neuroscience, and Zengqiang Yuan, PhD, an HMS research fellow in pathology, in collaboration with Keith Blackwell, MD, PhD, HMS associate professor of pathology, have now defined how a molecular chain-of-events links oxidative-stress signals to cell death in brain neurons.
In the course of investigating the mechanisms of cell death in neurons from rat brain, the team focused their attention on the function of a protein called MST, which had been previously implicated in cell death. They found that exposure of brain neurons to oxidative-stress signals stimulates the activity of MST, and once activated, MST instructs neurons to die. The researchers also found a tight link between MST and another family of molecules called FOXO proteins. FOXO proteins turn on genes in the nucleus, the command center of the cell. Once stimulated by oxidative stress, MST acts in its capacity as an enzyme to modify and thereby activate the FOXO proteins, instructing the FOXO proteins to move from the periphery of the cell into the nucleus of neurons. Once in the nucleus, the FOXO proteins were found to turn on genes that commit neurons to programmed death.
The discovery of the MST-FOXO biochemical switch mechanism fills a gap in our understanding of how oxidative stress elicits biological responses in neurons, and may include besides cell death, neuronal dysfunction and neuronal recovery. Since oxidative stress in neurons and other cells in the body contribute to tissue damage in a variety of disorders, including stroke, ischemic heart disease, neurodegenerative diseases, and diabetes, identification of the MST-FOXO switch mechanism could provide potential new targets for the diagnosis and treatment of many common age-associated diseases.
HARVARD MEDICAL SCHOOLhttp://hms.harvard.edu/Harvard Medical School has more than 7,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, the CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
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