Synaptic Actin Signaling Pathways in Fragile X

With a $163,000 grant from the FRAXA Research Foundation, Dr. Scott Soderling and Dr. Hwan Kim bred the standard mouse model of Fragile X syndrome to their lines of mice that express reduced levels of several key proteins that modulate synaptic actin. These compound mutant mice were compared to FXS mice to determine if genetically impairing pathways to the actin cytoskeleton can rescue deficits in the FXS mice.

$163,356 Grant
Scott Soderling, PhD
Principal Investigator

Hwan Kim, PhD
FRAXA Postdoctural Fellow

Duke University
2010-2012 FRAXA Research Grant
$163,000 over 2 Years

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. 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

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