Recent clinical trials involving Fragile X Syndrome (FXS), a genetic disorder that causes mild to severe intellectual disability, indicate that potential drug treatments are not as effective as researchers initially hoped. This lack of therapeutic potential suggests there are some gaps in our understanding of the neural mechanisms at play in FXS patients. Thanks to a new grant from the National Institute of Mental Health, University of Illinois professors Nien-Pei Tsai and Kai Zhang will explore the underlying synthesis of proteins related to FXS pathology in an effort to develop a thorough understanding of the disease.

The five-year, nearly $2 million project is called, “Mechanism of Gp1 mGluR-dependent translation and plasticity,” and will be led by Tsai, an associate professor in the Department of Molecular and Integrative Physiology, and Kai Zhang, an assistant professor in the Department of Biochemistry, both in the School of Molecular and Cellular Biology.

Professors Nien-Pei Tsai (left) and Kai Zhang (right)
Professors Nien-Pei Tsai (left) and Kai Zhang (right)

“This proposal brings together two labs with distinct expertise to study Fragile X Syndrome. I am excited that the funding from NIH will make this collaboration happen,” Tsai said.

The activation of Group 1 metabotropic glutamate receptors (Gp1 mGluRs) mediate translation-dependent synaptic plasticity, including long-term synaptic depression (LTD), though the mechanism is not completely understood. Gp1 mGluRs and their associated signaling are dysregulated in several neurological disorders, including FXS. Initial research done by the Tsai Lab discovered ubiquitin E3 ligase Murine double minute-2 (Mdm2) as a novel translational repressor that participates in Gp1 mGluR-induced translation. Mdm2 is well studied in cancer biology, however, Tsai’s group was the first to discover the dysregulation of Mdm2 in FXS murine models and the role of Mdm2 in Gp1 mGluR signaling, making it a potential target for FXS.

Because of the therapeutic potential of the protein, this promising research will further study how alterations of Mdm2 impair Gp1 mGluR signaling in FXS. Tsai hopes that these results, in conjunction with the existing knowledge of Mdm2 in cancer, can broaden our understanding of the protein’s role in neurological disorders.

“We hope our research can ultimately improve the future development of therapies for Fragile X Syndrome,” Tsai said.