|Defective Cyclic AMP Signaling in Fragile X
Cyclic AMP (cAMP) is a second messenger involved in many brain processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in Fragile X, the most common heritable cause of mental impairment and autism. This team is finding evidence of altered cAMP cascade function in Fragile X and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism with Fragile X from autism per se and the cAMP cascade may be a viable therapeutic target for both Fragile X and autism.
by Anita Bhattacharyya, 4/1/2007
Fragile X syndrome is defined by the loss of fragile X mental retardation protein (FMRP). We are exploring how cellular processes are affected by the loss of FMRP in brain cells, in hopes of identifying pathways to target for potential therapeutics.
Cells respond to signals (e.g. electrical, chemical signals) by signaling cascades that relay information from the outside of the cell to the nucleus where changes in genes occur. We want to test how the loss of FMRP affects a neural cell's signal transduction cascades. One signal transduction relay molecule that has been implicated in Fragile X is cyclic AMP (cAMP). Previous work by Fragile X researcher Elizabeth Berry-Kravis and colleagues showed that cAMP is lower in blood cells from Fragile X individuals. We have found that cells of the nervous system are also not able to produce cAMP as well in Fragile X. Lowered cAMP signal transduction affects how FX cells in the brain respond to stimuli and how they function during development.
In this project, we want to understand why cAMP production is lower in Fragile X. How does the lack of FMRP cause lower cAMP signaling? Is there a link between defective cAMP production and another signal cascade linked to FX, the mGluR pathway? Finally, using a drug assay on human FX cells, we hope to find compounds that can rescue the cAMP defect in Fragile X cells.