Charness and his team went on to develop multiple cell lines from that first culture, and that's where they encountered the riddle: In some of those lines, alcohol disrupted L1's adhesive effect, while in others it did not.
"How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?" asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.
Clearly, something else was affecting the protein's sensitivity to alcohol but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. "That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition," Charness said.
In the current study, Charness' team and collaborators at the University of North Carolina School of Medicine in Chapel Hill conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules. They focused on what was happening to the L1 molecule inside a cell that could affect an event outside the cell such as disruption by alcohol.
"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," said Xiaowei Dou, HMS instructor in neurology in the Charness Lab and first author on the new study. "Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal port
|Contact: David Cameron|
Harvard Medical School