UQ team helps tap into the alcoholic brain

Researchers at the University of Queensland have discovered fundamental differences in patterns of gene expression in alcoholic versus normal brains.

Using DNA microarrays to compare patterns of gene expression in post-mortem alcoholic and normal brain tissues, Assoc Prof Peter Dodd's research team has found evidence the supposedly benign 'social drug' may be less benign than believed.

Dodd's team at UQ's School of Molecular and Microbial Sciences and its US collaborators were recently awarded a second, five-year, US National Institutes of Health grant for alcoholism research, worth $1.23 million. Dodd said pre-frontal regions of the brain involved in executive control, social interaction and other higher mental functions appear to particularly sensitive to alcohol-induced neuronal death.

The focal regions of abnormal gene expression map closely to those identified by the UQ team's collaborators at the University of Bristol, who used positron-emission tomography (PET) scans to compare patterns of brain activity in alcoholics and non-alcoholics.

Dodd said the finding was unsurprising, given that most neurodegenerative disorders like Alzheimer's disease, motor neuron disease, Parkinson's disease and Huntington's disease tend to cause localised rather than global neuron death.

While alcohol perfuses the entire brain, it selectively damages areas with a particular cellular and molecular type -- Dodd said his team is working to identify the specific molecular signature associated with susceptibility to alcohol damage.

He said the toxic effects seen in the alcoholic brain might not due to alcohol, but to its breakdown product, aldehyde. But some of the changes involve genes with alcohol-responsive promoters, including genes coding for transcription factors.

Transcription factors coordinate the activity of complex genetic networks, so alcohol may damage susceptible neurons by inducing major, abnormal changes gene activity, ending in 'cellular suicide' or apoptosis.

One of the major changes, Dodd said, involves dysregulation of genes coding for the five protein sub-units that assemble in different combinations to make as many as 23 forms of GABA (gamma-amino butyric acid) receptors.

Acting through these receptors, the neurotransmitter GABA protects neurons against hyper-stimulation by its opposite number, glutamate, which can send them spiralling into apoptosis.

Dodd said some GABA sub-unit genes -- most notably, the alpha-1 sub-unit gene -- have alcohol-responsive elements in their promoters. He said molecular geneticists have shown that, in transgenic rats, chronic exposure to alcohol increases expression of the alpha-1 sub-unit in the pre-frontal cortex, altering its abundance relative to the alpha-3 subunit.

This 'sub-unit' switching leaves cells with GABA receptors that are less responsive to GABA - and thus, more vulnerable to over-excitation by glutamate.

"It was diametrically opposite to the result they expected," Dodd said. "But it is just what we predicted, because they had attached a human promoter to the rat's alpha-1 sub-unit gene, so it now contained an alcohol-responsive element. It was a very exciting result.

"GABA receptors are present in virtually every cell in the brain, so if you remove the inhibitory control in specific regions, they become selectively vulnerable to alcohol damage.

"The key to understanding alcohol damage is that the inefficient GABA receptors are present in those regions of the brain where we see neuronal death."

Dodd said the loss of neurons in these pre-frontal regions ranges up to 20 per cent -- a much less dramatic loss than seen in neurodegenerative disorders like Alzheimer's and Parkinson's, and consonant with the relatively mild, long-term decline in brain function seen in alcoholics.

"The really interesting thing is that the 30 post-mortem brains we have analysed, the patterns of gene expression we are seeing completely separate alcoholics from controls. All alcoholics fall in one bin, and controls in the other.

"Without pre-judging whether alcohol or an alcohol metabolite is the toxic agent, we can see a distinctive change in patterns of gene expression.

"For a disease that is generally considered to be mild in its effects, relative to something like Alzheimer's disease, we wouldn't have expected to see such a clear-cut distinction between the experimental and control groups.

"If the problem does arise in genes with alcohol- or aldehyde-responsive promoters, we can start to look at the genetic changes downstream, and the involvement of other factors such as the alcoholic's nutritional status."