Scientists identify molecular events that underlie FASD

Scientists have identified a molecular signaling pathway that plays an important role in the development of fetal alcohol spectrum disorders (FASD). The new research in cells and mice, supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, points to candidate genes for FASD susceptibility and may open new avenues for developing drugs to prevent alcohol damage to the fetal brain. A report of the study is now online in the journal Proceedings of the National Academy of Sciences.
“Prenatal alcohol exposure is the leading preventable cause of birth defects and developmental disorders in the United States,” says NIAAA Acting Director Kenneth R. Warren, Ph.D. “These new findings are yet another important contribution from researchers who have been at the forefront of scientific discovery in FASD.” Dr. Warren notes that FASD can include the distinct pattern of facial features associated with fetal alcohol syndrome (FAS) as well as intellectual disabilities, speech and language delays, and poor social skills.
The new study was led by Michael Charness, M.D., of the Veterans Affairs Boston Healthcare System and Department of Neurology, Harvard Medical School. It builds on previous work in which he and colleagues from the University of North Carolina Bowles Center for Alcohol Studies have described molecular and cellular events involved in alcohol’s disruption of brain development.
Fetal cells destined to become the brain and nervous system attach to each other with the help of L1 cell adhesion molecules. The cells come together when L1 molecules on the surface of one cell link up with L1 molecules on another. Dr. Charness’ group has also demonstrated that certain experimental compounds can block alcohol’s inhibition of L1 adhesion and thereby prevent alcohol-related fetal damage in mice.
“Our group has previously shown that alcohol inhibits the developmentally critical L1 cell adhesion molecule,” says Dr. Charness, who is also faculty associate dean at Harvard Medical School and assistant dean at Boston University School of Medicine.
In the current study, Dr. Charness and his colleagues conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules.
One area the researchers examined was phosphorylation. Phosphorylation plays a significant role in a wide range of cellular processes. By adding a phosphate group to a protein or other molecule, phosphorylation turns many protein enzymes on and off, and thereby alters their function and activity.
“We found that phosphorylation events that begin inside the cell can render the external portion of the L1 adhesion molecule more vulnerable to inhibition by alcohol,” says Dr. Charness. “Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal portion of the L1 molecule.”
The researchers also found that variations in ERK2 activity correlated with differences in L1 sensitivity to alcohol that they observed across cell lines and among different strains of mice. Dr. Charness and his colleagues note that these variations suggest that genes for ERK2 and the signaling molecules that regulate ERK2 activity might influence genetic susceptibility to FASD. Moreover, the identification of a specific locus that regulates the alcohol sensitivity of L1 might facilitate the rational design of drugs that block alcohol neurotoxicity.
The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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Reference:
Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule Xiaowei Dou, et al. Proceedings of the National Academy of Sciences (February 20, 2013)

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