Fragile X syndrome (FXS), caused by the inherited loss of the Fragile X Mental Retardation Protein (FMRP), is the most common form of inherited intellectual disability and the leading monogenetic cause of autism. FMRP is an mRNA binding protein that binds numerous mRNAs and often represses their translation. FMRP is detected at postsynaptic sites within dendritic spines where it is believed to play a role in local protein synthesis involved in synapse development and synaptic plasticity underlying learning and memory. Our long-term objectives are to characterize mechanisms of local protein synthesis in neurons, elucidate their functions in synapse development, and use this knowledge to develop strategies to restore synaptic protein homeostasis in fragile x syndrome and other neurodevelopmental disorders. A critical gap is lack of understanding of the underlying mechanisms of FMRP mediated regulation of local protein synthesis and how dysregulated translation may contribute to impaired synaptic protein homeostasis and dendritic spine development in fragile x syndrome. We hypothesize that FMRP is necessary for the activity dependent regulation of mRNA translation in dendrites and spines, and that loss of FMRP in FXS results in dysregulated translation and altered postsynaptic protein homeostasis leading to impaired synaptic development. To accomplish these goals, we will develop and employ novel fluorescent reporters and imaging assays to visualize and characterize novel mechanisms of FMRP mediated local protein synthesis in live cultured hippocampal neurons.
Aim 1 will test the hypothesis that loss of FMRP in a mouse model of FXS results in dysregulation of mRNA translation in dendrites and spines.
Aim 2 will test the hypothesis that loss of either FMRP, or mRNA target sequences involved in local protein synthesis, results in dysregulation of protein ubiquitination and homeostasis in dendrites and spines. The characterization of dysregulated protein homeostasis at synapses in fragile x syndrome has broader significance toward elucidation of the shared neurobiology of synaptopathies in autism spectrum disorders. This research will provide methods and rationale to assess other autism disease models and test therapeutic strategies that restore synaptic protein homeostasis.
Fragile x syndrome is the most common form of inherited intellectual disability and the most common monogenic cause of autism and there are no disease mechanism targeted treatments. This research will characterize impairments in molecular dynamics at synapses in mouse of fragile x syndrome and to potentially identify novel therapeutic strategies.
|Gross, Christina; Hoffmann, Anne; Bassell, Gary J et al. (2015) Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back. Neurotherapeutics 12:584-608|
|Suhl, Joshua A; Muddashetty, Ravi S; Anderson, Bart R et al. (2015) A 3' untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR. Proc Natl Acad Sci U S A 112:E6553-61|
|Ifrim, Marius F; Williams, Kathryn R; Bassell, Gary J (2015) Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome. J Neurosci 35:7116-30|