Angela Giangrande, Principal Investigator
Universite Louis Pasteur, Strasbourg
$45,000 in July 2004

The normal function of FMRP, the protein missing in Fragile X, involves two primary actions:

1. regulation of protein synthesis in dendrites, and
2. transport of messenger RNA from the nucleus of the cell to the dendrites.

Both these functions require significant interactions with the cytoskeleton, the scaffold which holds the cell together. In the first instance, cytoskeletal changes (dendritic spines become long and thin) occur whenever LTD (Long Term Depression) occurs, and this is known to occur too much in Fragile X. In the second case, transport of mRNA requires that FMRP hook onto the cytoskeleton and propel itself along, like a railroad train, to transport the mRNA to the dendrite, where it will be used as the template for protein synthesis. Clearly, these two functions are closely related, and both appear to be stimulated by activation of metabotropic glutamate receptors.

While much interest has been focused on the signaling pathways connected to mGluR’s, these interactions with the cytoskeleton may have important implications for understanding the basic mechanisms of Fragile X. Dr. Giangrande will investigate these interactions in detail in fruit flies, which are a simple yet powerful system in which multiple genes can be manipulated with relative ease.