Scientists discover how brain turns on system designed to protect nerve cells fr

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Scientists discover how brain turns on system designed to protect

nerve cells from toxic " free radicals "

http://www.news-medical.net/?id=20654

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. "

http://www.dfci.harvard.edu