The National Institutes of Health has awarded a $9.5 million grant to Professor of Molecular Medicine Joel D. Richter, PhD, and colleagues to establish a Center for Collaborative Research in Fragile X at UMass Medical School, one of three centers designated by the NIH. Scientists at the centers will seek to better understand the Fragile X syndrome and its associated disorders in an effort to work toward developing effective treatments for the inherited illness. In total, the NIH awarded $35 million to the centers.
Dr. Richter is principal investigator on the 5-year grant that includes his colleagues Gary J. Bassell, PhD, professor of cell biology at Emory University, and Eric Klann, PhD, professor of neural science at New York University. Together, the trio will explore the underlying molecular basis of the Fragile X disorder, focusing on messenger RNA (mRNA) translational control.
“Fragile X syndrome arises when a single gene is inactivated,” said Richter. “That indirectly causes protein synthesis in the brain to be elevated, which likely causes the disease. What we want to investigate is how that protein synthesis comes about and how rebalancing it can rescue or reverse the illness in mice so the animals no longer have the Fragile X syndrome.”
Fragile X is the most common form of inherited intellectual and developmental disability. It can affect one in about 4,000 males and one in about 6,000 females. People with Fragile X suffer from intellectual disability as well as behavioral and learning challenges ranging from mild to severe. As many as 30 to 50 percent of people with the Fragile X syndrome also have disease features that are found on the autism spectrum.
An expansion of a CGG trinucleotide repeat in the DNA of the FMR1 gene causes the Fragile X syndrome. The Fragile X protein made from this gene is most commonly found in the brain and helps create and maintain plasticity. It is also needed for normal neurological development. The longer this CGG repeats the more severe the disabilities.
While the Fragile X protein has several functions in the brain, its primary role is to slow down the molecular machinery that translates mRNAs into mature proteins. Without the Fragile X protein, these machines run out of control. The result is excessive amounts of perhaps 1,000 or more different proteins in the brain of a Fragile X patient.
It is thought that this inability to repress mRNA translation, which in turn leads to an increase in neural proteins in the brains of Fragile X patients, somehow hampers normal synaptic function. But because the Fragile X protein interacts with so many mRNAs, and some proteins become more elevated than others, parsing which mRNA or combination of mRNAs is responsible for Fragile X is a daunting task.
Working together, Richter and his collaborates will investigate three molecules that have been shown to slow down mRNA translation in the absence of the FMR1 gene and restore biochemical balance, as well as cognitive and behavioral functioning, in mice. By learning which proteins are commonly impacted by all three molecules, they hope to identify possible therapeutic targets for Fragile X syndrome.
“In previous studies we’ve shown that we can reverse or rescue the Fragile X syndrome and restore nearly normal behavior and certain biochemical abnormalities in mice,” said Richter. “We don’t know if there are hundreds or thousands of proteins working in concert that cause the syndrome or whether there are only a few key proteins whose aberrantly excessive levels elicit disease characteristics. We want to investigate how this process works initially in mice and then in humans, which will hopefully lead to new treatments for this disease.”
Other UMMS investigators on the study include John L. Sullivan, MD, professor of molecular medicine, and Manuel Garber, PhD, associate professor of molecular medicine and director of the bioinformatics core at UMMS.
The Centers for Collaborative Research in Fragile X was originally established in 2003 as a result of the Children’s Health Act of 2000. Three centers were funded in 2013; in addition to the one at UMMS, other collaborative centers are at the University of Texas Southwestern Medical Center in Dallas and Emory University in Atlanta.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke are contributing funding and scientific expertise for the collaborative centers.