|
 |
|
      |
|
|
|
 Research & Giving News Article  Linked to Autism Sticky blood protein yields clues to the illness In an article appearing in the March issue of the Journal of Clinical Investigation, Ana Carneiro, Ph.D., a 2007 NARSAD Young Investigator, and colleagues at Vanderbilt University Medical Center, report that a well-known protein found in blood platelets called integrin beta3 physically associates with and regulates a protein called the serotonin transporter, or SERT, which controls serotonin availability. Serotonin has long been suspected to play a role in autism via elevated blood serotonin levels and genetic variations in SERT. Alterations in brain serotonin have also been associated with anxiety, depression and alcoholism. Antidepressants that block SERT, known as SSRIs, or selective serotonin reuptake inhibitors, block the molecule’s ability to sweep synapses clean of serotonin. Looking for serotonin in platelets Working in the lab of NARSAD Scientific Council member Randy Blakely, Ph.D., Dr. Carneiro was searching for proteins that interact with SERT and might contribute to disorders where serotonin signaling is altered. “Levels of SERT in the brain are actually quite low, so we decided to see what progress we could make with peripheral cells that have much higher quantities,” said Dr. Blakely, the Allan D. Bass Professor of Pharmacology and director of the Vanderbilt Center for Molecular Neuroscience at Vanderbilt University Medical Center. “This took us to platelets.” Platelets are the sticky cells that combine to form blood clots. In platelets, SERTs accumulate serotonin that is produced in the gut. Administration of SSRIs or genetic suppression of the SERT protein in animals has been observed to prevent serotonin uptake in platelets. “Prior research had fingered the integrin beta3 gene as a determinant of blood serotonin levels and, independently, as a risk factor for autism,” Dr. Blakely said. Integrin beta3 activation enhances serotonin uptake In the new study, Dr. Carneiro identified a large set of proteins that “stick” to SERT, hypothesizing that they might control SERT activity. One of these turned out to be integrin beta3. Once Drs. Carneiro and Blakely confirmed a physical relationship between the two proteins, they investigated whether the interaction can change SERT activity. They found that cells lacking integrin beta3 took up less serotonin and that integrin beta3 activation or a human integrin beta3 mutation greatly enhances serotonin uptake. “We found that integrin beta3 can put the serotonin transporter into high gear,” said Dr. Blakely. Notably, Scientific Council member Edwin Cook, M.D., at the University of Illinois at Chicago and a co-author on the study, had previously shown that the same integrin beta3 mutation that elevates SERT activity also predicts elevated blood serotonin. “Most investigators studying this integrin beta3 mutation have focused on how its high activity state changes platelet clotting and never looked at its impact on serotonin levels or SERT function,” explained Dr. Carneiro. “Now they have a reason to.” “We don’t think the platelet itself contributes to autism,” Dr. Blakely clarified, “but rather we believe that the brain’s serotonin transporter may be controlled by integrin proteins in a very similar manner.” Elevated SERT activity and autism Drs. Carneiro and Blakely believe that too much SERT activity imposed by abnormal integrin interactions could restrict availability of serotonin in the brain during development, as well as in the adult. “What is even more striking is that this is the second time we have found elevated SERT activity associated with autism,” said Dr. Blakely. In a 2005 study, Blakely and Vanderbilt collaborator James Sutcliffe, Ph.D., identified mutations in the SERT gene that triggered elevated SERT activity. Dr. Carneiro is now hot on the trail of integrin interactions with brain SERT and is engaged in engineering mice that express human integrin beta3 mutations. “These new animal models offer an unprecedented opportunity to peel away the complexity of autism and possibly develop new therapies,” Dr. Blakely commented. The research also may uncover new ways of treating depression. “Current antidepressant mechanisms still essentially work in the same way they did 25 years ago – by targeting transporter uptake of neurotransmitter [i.e., serotonin] directly,” Carneiro said. “Now we may have a completely new way to go about it.” This article was adapted by NARSAD with permission of Vanderbilt University Medical Center. Randy Blakely and Edwin Cook are SC members. |
Media Contact
Upcoming NARSAD Events
Latest News from NARSAD
Spotlight
|
|
For the Media