Fragile X syndrome is a genetic disorder that causes intellectual disability and autistic symptoms. Fragile X is caused by epigenetic silencing of the Fmr1 gene, which results in the loss of Fragile X Mental Retardation Protein (FMRP). FMRP is highly expressed in neurons, where it can bind to hundreds of different mRNAs and thereby decrease their rate of translation. In addition, loss of FMRP causes a general increase in mRNA translation through secondary effects that act on the translational machinery. The effects of FMRP loss on neuronal translation contribute to structural and functional deficits in synapses and impaired cognition in the Fragile X mouse model, and are therefore considered a central component of Fragile X pathophysiology. In addition to their presence in neuronal soma, FMRP and many of its target mRNAs also localize in neuronal dendrites. This raises the question whether the increased translation resulting from FMRP loss preferentially impacts dendritic or somatic translation. As the effects of FMRP loss on mRNA translation should profoundly alter the ribosome-association of affected mRNAs, we propose a genome-wide analysis of the in-vivo ribosome- association of dendritic and somatic mRNA in the absence of FMRP. For this we will use a novel method for the separate collection of in-vivo ribosome-associated mRNA from the dendrites and soma of CA1 pyramidal neurons. This exploratory proposal will make a number of contributions. First, it will perform the first analysis of in-vivo subcellular changes in translaton in a Fragile X model. Second, it will identify which dendritic and somatic mRNAs are affected at the translational level in the absence of FMRP, thereby identifying potentially novel therapeutic targets and pathways. Third, it might establish altered ribosome-association as a molecular endophenotype of the Fragile X mouse model. Fourth, it will set the stage for future studies that analyze dendritic and somatic ribosome-bound mRNA in mouse models for other types of autism and intellectual disability, which might lead to the discovery of shared molecular mechanisms among these brain disorders.
Fragile X syndrome is a genetic disorder that causes the loss of Fragile X Mental Retardation Protein (FMRP) in neurons, which results in intellectual disability and autistic symptoms. FMRP is located in different compartments of the neuron, and it is unclear how FMRP loss impacts these different compartments. This proposal will investigate the molecular effects of FMRP loss in two major neuronal compartments, the soma and the dendrite.
