Download Giuseppe Minniti, MSc, City University of New York – College of

(Recent Photograph)
Ethanol Modulates Gene Expression in the Brain by Activating the Heat Shock Pathway
Petr Protiva, MD, Ph.D., Yale Univ. School of Medicine, New Haven; and Veterans Affairs Healthcare System, West
Haven, CT
Giuseppe Minniti, MSc, City University of New York – College of Staten Island, NY
Leonardo Pignataro, Ph.D., Columbia University; City University of New York – College of Staten Island, NY
Presenter
Leonardo Pignataro, Ph.D., Columbia University; City University of New York – College of Staten Island, NY
Chronic alcohol drinking causes profound physiological adaptations, which lead to physical dependence and
tolerance. Some of these adaptations result from a complex chain of events that occur in the brain, long before a
state of alcohol dependence is reached. Studies performed in animal models demonstrated that brief exposure to
alcohol modifies the expression of various genes. This modulation of gene expression seems to be the underlying
molecular mechanism responsible for the alteration of the brain circuits that result in tolerance and dependence.
Although many alcohol-responsive genes have been identified; little is known about the mechanism/s through
which alcohol modulates their expression. The current research demonstrates that physiological concentrations of
ethanol (10-60mM) alter gene expression through the activation the heat shock cascade and the transcription factor
heat shock factor 1 (HSF1) in both cortical neurons and glial cells. More specifically, we revealed that the ethanol
activation of HSF1 results in the translocation of this transcription factor into the nuclei of cortical neurons and glial
cells. This transcriptionally active factor binds to a novel DNA cis-acting regulatory element, present in the alcoholresponsive genes; a sequence that we named the alcohol response element (ARE). Results from microarray analysis
of cortical neurons revealed that alcohol-induced genes are involved in synaptic transmission, neurotransmitter
release, presynaptic calcium sensing, synaptic vesicle docking, synapse formation and plasticity. Alterations of this
set of genes in neurons can explain the physiological changes that occur in the brain of alcoholics. Other genes
activated by alcohol in neurons included: ethanol metabolism, oxidoreductase activity, insulin-like growth factor
signaling, acetyl-CoA, and lipid metabolism genes. Finally, the microarray analysis conducted in astrocytes indicated
that ethanol increased the expression of glial-specific immune-response genes, as well as genes involved in
transcription regulation, proliferation, and differentiation. These results suggest that ethanol activates the immune
response and causes oxidative stress in the glia and it can provide an explanation for the inflammatory cell damage
typically observed in the brains of alcoholics.
What will the audience take away from your presentation?
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The audience will gain a deeper understanding of the molecular adaptive mechanisms triggered by alcohol
that lead to tolerance and dependence.
This work can help identify pharmacological opportunities for novel therapeutics to treat patients at risk of
developing alcohol dependence.
This research will allow investigator and teachers to explain the physiological and psychological changes
observed in alcoholic individuals.
The genes indentified by microarray analysis can explain the massive brain cell loss observed in alcoholics.
This can help investigators to identify targets for clinical invervetions in patients.
Scientific Session: 1. NEURODEGENERATIVE DISORDERS
Biography of presenting author
Dr. Pignataro completed his graduate studies at the University of Buenos Aires in Argentina and University of
Alberta in Canada. After finishing his Ph.D. in Neuroscience, he moved to Chicago to become a Postdoctoral
Associate at Feinberg School of Medicine of Northwestern University where he studied the physiology of glutamate
transporters in the retina. In 2004, he moved to NYC and joined the laboratory of Dr. Neil Harrison at Weill Cornell
Medical College to study the alcohol-induced genomic mechanism of plasticity in the brain. In 2008, Dr. Pignataro
moved to Columbia University as an Assistant Professor where he extended his work on the effects of alcohol on
gene expression to the glia. He is currently and Assistant Professor at the City University of New York.
Author Details
Leonardo Pignataro, Ph.D., Columbia University; City University of New York – College of Staten Island, NY
Ph: +1 917-881-8241
Oral presentation
1. NEURODEGENERATIVE DISORDERS
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