Free Radical Cell Death Switch Identified

Main Category: Seniors / Aging News
Article Date: 02 Jun 2006 - 20:00pm (PDT)

"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 SCHOOL

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.

John Lacey
public_affairs@hms.harvard.edu
Harvard Medical School
http://www.hms.harvard.edu

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