Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in children. There is no cure for FXS and no drug has been approved to treat its cause or symptoms. FXS is caused by loss of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein that has been implicated in the control of synaptic development and plasticity in the wild-type brain. FMRP acts as a translational regulator, and is conventionally thought to repress mRNA translation at the level of initiation and elongation. FMRP is actively transported to distal axons and dendrites while associated with RNAs and RNA binding proteins in large cytoplasmic ribonucleoprotein particles (RNPs). One abundant population of FMRP-containing RNPs is enriched for components of cytoplasmic RNA processing bodies (P-bodies). P-bodies are highly conserved RNPs that are involved in mRNA deadenylation followed by translational repression or decapping and 5' to 3' decay. Published observations suggest that FMRP-containing P-bodies (FMR/P-bodies) may play a critical role in the control of synaptic development and plasticity. It has been proposed that the primary function of FMRP at synapses is to repress dendritic mRNA translation and this has been the focus of most research efforts in the FXS field. However, a growing amount of data indicates a critical presynaptic function for FMRP in the control of FXS phenotypes. Our preliminary data suggests that presynaptic FMR/P-bodies may be involved in the control of RNA metabolism homeostasis by directing targets into deadenylation and/or decay pathways. Based on this, we hypothesize that the FMRP protein interacts biochemically and genetically with components of these pathways to control translation and axon terminal growth at the Drosophila larval NMJ. To test this hypothesis, we propose the following three Specific Aims.
Aim 1 will test the hypothesis that neuronal P-body proteins control synaptic development.
Aim 2 will test the hypothesis that P-body proteins colocalize with FMRP in larval motoneuron axons.
Aim 3 will test the hypothesis that neuronal P-body proteins interact both biochemically and genetically with FMRP to control synaptic development. The work proposed in these aims is expected to clarify a novel molecular mechanism by which the FMRP protein coordinates with P-bodies to regulate translation of targets involved in the control of neuroplasticity.
TO HUMAN HEALTH: Many of the phenotypes associated with FXS are likely caused by the dysregulation of specific mRNAs encoding for proteins involved in the control of plasticity processes. Moreover, relatively little is known the role of presynaptic FMRP in FXS. Thus, we predict that identification of these evolutionarily conserved mechanisms will eventually provide researchers with novel targets for the diagnosis, prevention, and/or treatment of human neurological disorders including FXS. R15-SPECIFIC OUTCOMES: This work will be done entirely by graduate and undergraduate students, thus addressing one of the main objectives of the R15 AREA Grant mechanism.
