Lorna Farrelly, PhD, and Ian Maze, PhD
Serotonin, a powerful chemical that sends signals between nerve cells in the brain, has long been thought to play a key role in processes such as appetite, mood, and sleep. Now, research by neuroscientists at the Icahn School of Medicine at Mount Sinai suggests that the molecule can also enter the nucleus of these cells and help turn genes on. It is a surprising discovery that has the promise to yield fundamental new knowledge about addiction, mood disorders, and neurodegenerative diseases such as Parkinson’s disease.
The findings, which were recently published in the journal Nature, are a divergence from conventional thinking that neurotransmitters have one role—which is to bind to nerve cells and send signals that change these cells’ activity.
“We have shown that there is a novel role for neurotransmitters in the brain that is independent of neurotransmission, but critically important to their overall signaling,” says Ian Maze, PhD, Assistant Professor of Neuroscience, and Pharmacological Sciences, and senior author of the multicenter study. “It suggests that our current understanding of these molecules is incomplete and requires further investigation.” Study authors also included postdoctoral fellow Lorna Farrelly, PhD.
The study involved DNA, the blueprint for all cell functions in the body. Each cell contains two strands of DNA that are packaged by histone proteins and arranged in spools known as nucleosomes. The tighter the DNA is wound into nucleosomes, the less likely that genes being encoded will be turned on, or expressed; when it is not wound as tightly, genes are more likely to be expressed.
Based on previous research that had found large pools of neurotransmitters in the nucleus of neurons and suspecting that this could result in additional, neurotransmission-independent functions for these chemicals, Dr. Maze and his team hypothesized that certain nuclear proteins may be modified by these molecules to affect their functions. They discovered that a protein, tissue Transglutaminase 2, can directly attach serotonin molecules to histone proteins, a process called histone serotonylation. Once the serotonin is attached, stronger expression of genes associated with these modified histones is observed.
They also demonstrated that these serotonyl marks on the histone protein help draw other proteins that play a key role in increasing gene expression. “We found that these marks hyper-recruit one particular factor, Transcription factor II D, that enables the genes to turn on,” Dr. Maze says. “That provides some mechanistic insight into how these marks may be influencing gene expression.”
In a blog entry summarizing these findings, Francis S. Collins, MD, PhD, the Director of the National Institutes of Health, wrote, “While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.”