With a 2-year, $90,000 grant from FRAXA Research Foundation in 2016, Dr. Samie Jaffrey from Weill Medical College of Cornell University will research which FMRP is right for therapeutic development of fragile X syndrome.
A major challenge in developing therapeutics for fragile X syndrome is the fact that normally there are many forms of the fragile X protein (FMRP). This one protein regulates various pathways in different cell compartments of both neuronal and non-neuronal cells. It is difficult to determine which FMRP-regulated pathway needs to be corrected to improve clinical outcomes in FXS.
To definitively answer the above questions, we propose to develop a highly robust method to selectively restore protein expression in a compartment-specific and cell-specific
manner of live animals and determine if this reverses synaptic and spine defects. Our long-term goal is to indentify druggable targets for FXS therapeutic development.
Molecular Mechanisms of Cytoskeletal Regulation by FMRP
One feature of neurons that display abnormalities in FMR1 is that dendritic spines have abnormal shapes. This suggests that FMR1 has a role in controlling the shapes of these spines. Since spines are key structures involved in learning, memory, and behavior, the abnormal structure of these spines may explain some of the features seen in patients with fragile X. What is unclear is how FMR1, which is known to regulate mRNA translation, controls the underlying cytoskeleton of dendritic spines.
We are investigating how FMR1 regulates an mRNA that encodes a critical regulator of the neuronal cytoskeleton called RhoA. RhoA has independently been shown to affect dendritic structure and its mRNA has been shown to interact with FMR1, thus suggesting an appealing connection between FMR1, RhoA, and spine abnormalities. If spine abnormalities are due to the inability of FMR1 to regulate RhoA, pharmacotherapy directed against RhoA or the RhoA molecular pathway may be suitable for reversing the symptoms of fragile X.