MariVi Tejada-Simon, PhD, Principal Investigator

FRAXA Awards:

Micheal Tranfaglia, MD; FRAXA, 11/3/2012

Dr. Tejada-Simon is investigating the role of the enzyme Rac1 in the pathology of fragile X. The seminal work of Dr. Kim Huber (currently of UT Southwestern) has shown that excessive signaling through metabotropic glutamate receptors (especially mGluR5) causes much of the brain dysfunction in fragile X. However, the "mGluR Theory of Fragile X" did not attempt to explain why the function of this pathway was found to be excessive. Indeed, it known that there is a normal amount of mGluR5 itself, and most components of the signaling pathway are also present in normal amounts. Dr. Tejada-Simon has shown that Rac1, the enzyme which initiates the signaling cascade following stimulation of metabotropic receptors, is increased in quantity and level of activity in fragile X, thus offering mechanistic support for the mGluR Theory, and an opportunity to target the specific abnormality in fragile X.

During the first year of this project, she characterized the extent of this abnormality and began testing compounds which can inhibit Rac1. In the second year of work, she will be thoroughly testing 3 major treatment strategies which inhibit Rac1, and assessing their ability to rescue the anatomic and behavioral deficits in the fragile X mouse model. Two of the compounds being tested are investigational agents, but the third is an available drug called a statin. Numerous statins are available as treatments for high cholesterol, such as lovastatin (Mevacor) and simvastatin (Zocor); these are well-tested drugs with an excellent safety profile, so this work offers the prospect of an off-the-shelf disease-modifying treatment for fragile X.

by MariVi Tehada-Simon, 6/8/2011

It is now well known that brains of FXS patients as well as those of FXS animal models display a higher density of immature dendritic spines. This morphological feature is thought to represent the basis for the cognitive and behavioral abnormalities associated with this disorder. A molecular link between the lack of FMRP and the production of a large number of immature dendritic spines is not clear, but our work and the work of others point to an involvement of the Rho family of small GTPases, proteins that mediate actin cytoskeleton reorganization, neuronal morphogenesis and gene expression.

Previous studies in our laboratory demonstrate that one of these small GTPases, Rac1, is critical for synaptic plasticity and dendritic spine development. Moreover, we have recently shown that Rac1 is altered in Fmr1 KO mice. Hyperactivity of Rac1 may well be responsible for the atypical dendritic spine morphology and other functional alterations in Fmr1 KO mice. Consequently, lowering Rac1 activity will likely rescue the atypical phenotypes identified in this animal model.

We expect that the pharmacological agents to be used in this study will enable us to focus on the identification of new targets for drug discovery and novel therapies for this disease.

by MariVi Tejada-Simon, 8/1/2008

It is well known that Rac, a member of the Rho family of small GTPases, plays a key role in the formation, maturation and maintenance of dendritic spines in neurons. Neuronal plasticity requires actin cytoskeleton remodeling and local protein translation in response to synaptic activity. The shape and density of actin-rich dendritic spines is altered in patients with Fragile X syndrome (FXS) as well as in Fmr1 knockout mice.

Recently it has been reported that FMRP (protein missing in Fragile X) has a connection to Rac at least in fibroblasts. In these cells, absence of FMRP induces an atypical development of actin remodeling by bringing up levels of proteins such as Rac, as well as Rac downstream effectors PAK, CYFIP1 and also PP2A. Consistent with these observations, specific neurons of transgenic mice that overexpress Rac showed an abnormal structure of their dendritic spines.

We believe that under normal conditions, FMRP may act as a negative regulator on the synthesis and/or transport of proteins involved in the actin cytoskeleton such as Rac. This function likely maintains an optimal level of the protein and facilitates the reorganization of the cytoskeleton leading to normal changes in neuronal morphology during activity-dependent plasticity. In contrast, in Fmr1 knockout mice (animal model of FXS), lack of FMRP may induce an excessive synthesis of Rac, leading to abnormal Rac-induced actin remodeling, which in turn may generate the anomalies reported in the structure and possibly in function of dendritic spines, resulting in cognitive deficiencies.

Our laboratory is testing this hypothesis using Fmr1 knockout mice model. If this alteration in Rac exists, we will determine whether pharmacological or genetic manipulation of Rac in these animals can rescue the cellular and behavioral abnormalities observed.