|Modification of Fragile-X Syndrome by Synaptic Actin Signaling Pathways
by Scott Soderling, 4/2/2010
It is generally accepted that Fragile-X Mental Retardation Protein (FMRP) normally functions at synapses (the sites of communication between neurons) to limit the translation or production of new proteins. This occurs downstream of the neurotransmitter glutamate via the metabotropic receptor mGluR5 and ultimately regulates changes in the strength of synaptic connections (synaptic plasticity).
Thus, Fragile-X Syndrome (FXS) due to the loss of FMRP is believed to be a disease of excess translation that ultimately leads to altered plasticity and mental retardation (Figure 1). There is a critical unmet need to understand the molecular mechanisms of how excess translation leads to FXS. Lack of such knowledge is an important problem because it hinders our ability to imagine how FXS may be corrected.
Our central hypothesis is that loss of FMRP leads to the deregulation of synaptic actin and that this is a significant molecular endpoint that is causal to the behavioral deficits in Fragile-X Syndrome. The rationale for this hypothesis is based on several lines of evidence.
1) Several of the mRNAs regulated by FMRP directly impact spine actin dynamics, including both the mRNA encoding the Rac GTPase, a key regulator of actin dynamics, and the mRNA encoding profilin, an actin binding protein.
2) PAK, a kinase that regulates the actin cytoskeleton downstream of Rac, also binds FMRP. Genetic inhibition of PAK in mice partially rescues Fragile-X Syndrome, demonstrating a functional link between Rac-PAK signaling, and FXS.
3) FMRP binds Cytoplasmic FMRP Interacting Protein (CYFIP). CYFIP also couples Rac to WAVE-1, an activator of spine actin polymerization. Our previous work has shown that WAVE-1 is an important actin regulatory protein that regulates dendritic spines (a component of the synapse) and synaptic plasticity. We have shown that several of the cellular phenotypes in the WAVE-1 mutant mice are opposite of those observed in the FXS mice, including reduced mGluR mediated synaptic plasticity and reduced spine density.
Our project will utilize a mouse model of FXS that will be bred to our lines of mice that express reduced levels of several key proteins that modulate synaptic actin. These compound mutant mice will be compared to FXS mice to determine if genetically impairing pathways to the actin cytoskeleton can rescue the behavioral or synaptic plasticity deficits in the FXS mice. Our hope is that genetically rescuing aspects of FXS will lead to new and useful therapeutic targets for treating Fragile-X Syndrome.