The genetic pathway

Dec 10, 2007 10:16 GMT  ·  By

Alcohol abuse can provoke a much more lasting damage on the brain and on other internal organs (liver, kidney, pancreas and so on).

Studies made on animals have revealed that alcohol can impede the development of new brain cells in adults. Heavy drinking during pregnancy can also impact the development of the baby's brain, provoking the fetal alcohol syndrome (FAS), associated with mental retardation.

But till now, how the alcohol did it was unknown. Now, a new study, at Weill Cornell Medical College in New York City and published in "Neuroscience", revealed how alcohol impacted genes involved in the activity of brain cells, explaining disorders caused by chronic alcoholism, and the abnormal brain development in FAS.

"If you are going to understand the biological effects of alcohol on genes within cells, you have to understand the molecular machinery driving the transcription, or activation, of the genes in question," said senior author Dr. Neil L. Harrison, professor of pharmacology and pharmacology in anesthesiology at Weill Cornell.

After studies made in cell cultures and in mouse neurons in vivo, the researchers discovered that alcohol turned on a common stress-linked genetic activity, called the heat shock pathway, and triggered by a molecule named heat shock factor 1 (HSF1) inside the brain cells. This molecule activates the transcription of many genes known to be shut on by alcohol.

The Gabra4 gene is known for long to control the activity of receptors for GABA, a crucial neurotransmitter.

"We knew that levels of expression of Gabra4 fluctuated rapidly in the presence of alcohol, and so we wondered if we could find out how this happens," said lead author Dr. Leonardo Pignataro, instructor in pharmacology in anesthesiology at Weill Cornell.

A Korean team had previously discovered in the C. elegans worm that alcohol acted on a DNA stretch, controlling the heat shock pathway, and the same DNA portion was found in the Gabra4 gene of mice and humans.

"This was all very intriguing, because the heat shock pathway is a biochemical mechanism found in almost all cells and all organisms. Scientists believe it helps cells deal with stressors -- including excessive heat or environmental toxins -- substances such as alcohol." said Harrison.

By using microarray technologies, the team found an array of genes, other than Gabra4, turned on by the heat shock pathway when exposed to alcohol.

"The big question that remains is how does this activation occur. The current theory holds that, under conditions of stress, heat shock proteins break away from a key molecule, HSF1. HSF1 then makes its way to the cell nucleus, where it helps stimulate the transcription and activation of a variety of genes that enable the cell to survive stress. We think this may happen with alcohol exposure," said Harrison.

The findings could be replicated in vivo experiments on mice.

"It was really exciting to see this mechanism work itself out in an animal model, suggesting that this same pathway may mediate at least some of the effects of alcohol on human brain cells," said co-author Dr. Daniel Herrera, assistant professor of psychiatry at Weill Cornell and an attending psychiatrist at NewYork-Presbyterian/Weill Cornell.

What those effects might exactly mean clinically remains in the realm of speculation for now, the researchers stress.

"Alcohol can have bad effects -- the well-known effects of alcoholism, such as liver or brain damage, for example -- but moderate alcohol use also has more benign effects, such as the improvement in cardiovascular health observed in drinkers of red wine compared with tee-totallers," said Pignataro.

Alcohol could stimulate the heat shock pathway, which erases cell-damaging mis-folded proteins, a beneficial effect.

"But it might also be possible that inappropriate activity of this pathway -- either during fetal brain development or in the adult brain -- is harmful," said Harrison.