free radicals
Dana-Farber Cancer Institute Released:
Scientists ID Switch for Brain’s Natural Anti-Oxidant Defense
Description
Scientists at Dana-Farber Cancer Institute report they have found how
the brain turns on a system designed to protect its nerve cells from
toxic “free radicals,” a waste product of cell metabolism that has
been implicated in some degenerative brain diseases, heart attacks,
strokes, cancer, and aging.
Newswise — Scientists at Dana-Farber Cancer Institute report they
have found how the brain turns on a system designed to protect its
nerve cells from toxic “free radicals,” a waste product of cell
metabolism that has been implicated in some degenerative brain
diseases, heart attacks, strokes, cancer, and aging.
Potentially, the researchers say, it may be possible to use drugs to
strengthen the anti-oxidant system in the brain as a treatment for
presently incurable diseases like Parkinson’s, Huntington’s, and
Alzheimer’s and possibly other maladies.
Dana-Farber’s Bruce Spiegelman, PhD, and colleagues, using a mouse
model, discovered that a regulatory protein, PGC-1a, switches on the
anti-oxidant system when free radicals, or reactive oxygen species,
begin to accumulate. It’s believed that some brain diseases involve a
failure of the protective system, and the authors report that turning
on PGC-1a to high levels in cultured cells protected them against
nerve toxins. The findings will be reported in the Oct. 20 issue of
the journal Cell.
“This could have broad implications for the many diseases in which
reactive oxygen species are implicated,” said Spiegelman. Anti-
oxidant supplements have been used with some success in patients with
neurodegenerative diseases, but Spiegelman noted that the process
sparked by PGC-1a “is how nature does it.”
Researchers currently are screening drugs in search of compounds that
could spur PGC-1a expression in brain cells, as well as exploring
whether any harmful side effects might result. PGC-1a is a
transcriptional co-activator discovered in Spiegelman’s Dana-Farber
laboratory in 1998. It has subsequently been found to play a master
regulatory role in metabolic processes and muscle function, as well
as being a culprit in diabetes.
The report establishes for the first time that PGC-1a both drives the
mitochondria to make energy and triggers the cleanup of toxic free
radicals that accumulate in the cell as byproducts. As excess free
radicals build up, their toxicity places the cell under “oxidative
stress,” which prompts the cell to produce more PGC-1a, which in turn
spurs the anti-oxidant defenses into action.
“With this mechanism, the body can speed up mitochondrial formation
and at the same time suppress the creation of reactive oxygen
species, which are known to be terribly damaging to the cell,”
explains Spiegelman, who is also a professor of cell biology at
Harvard Medical School. In this respect, the cell could be compared
to a self-cleaning oven — but one that becomes less efficient with
age and in certain diseases.
Therefore, the new finding of a specific regulator of the body’s own
anti-oxidant system could lead to more-effective treatments for a
number of diseases, and might even retard some of the effects of
aging, the researchers say.
In previous experiments, Spiegelman and others had bred mice that
lacked the PCG-1a gene. As would be expected, the absence of PCG-1a
caused the mice to have abnormalities in their metabolism — they had
less exercise capacity and were extremely sensitive to cold. But what
the scientists hadn’t predicted was that the mice had
neurodegenerative lesions in their brains and behaved abnormally:
This was a clue that without PGC-1a, the cells’ “self-cleaning”
mechanism wasn’t activated properly, leaving the mice more vulnerable
to brain damage from renegade free radicals.
In the current research, Spiegelman and his colleagues exposed normal
mice and rodents lacking PGC-1a to a nerve toxin that accelerates the
production of free radicals. Mice without PGC-1a suffered more brain
damage because they couldn’t turn on their anti-oxidant defenses.
Finally, to investigate whether increasing PGC-1a activity in the
brain would protect against oxidative stress, the scientists caused
mouse brain cells and human brain cells in the laboratory to make 40
times as much PCG-1a as normal. They exposed the cells to increasing
amounts of paraquat or hydrogen peroxide, chemicals that cause
oxidative stress and cell damage. The result: many more brain cells
survived the assault than did cells without the extra PGC-1a activity
to augment their defenses.
Because PGC-1a has now been shown both to rev up energy production in
the mitochondria and to suppress the resulting free radicals, “this
is an almost ideal protein to control or limit the damage seen in
neurodegenerative diseases that have been associated with defective
mitochondrial function,” the authors wrote. As a result, finding
drugs that increase PGC-1a in the brain “could represent a new mode
of therapy for a set of diseases that are both common and have only
marginal therapies at this moment.”
Lead authors of the report are Julie St-Pierre, PhD, and Stavit
Drori, PhD, formerly of Dana-Farber and Harvard Medical School. The
paper’s co-authors are based at Dana-Farber, Beth Israel Deaconess
Medical Center, and Harvard Medical School.
The research was funded in part by the National Institutes of Health.
Dana-Farber Cancer Institute (http://www.dana-farber.org) is a
principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United
States. It is a founding member of the Dana-Farber/Harvard Cancer
Center (DF/HCC), designated a comprehensive cancer center by the
National Cancer Institute.
