Spatial Translational Dysregulation in Fragile X Syndrome

About This Grant

PROJECT SUMMARY Fragile X syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). It is caused by a CGG trinucleotide repeat expansion in the 5’-UTR of the FMR1 gene, leading to the loss of fragile X messenger ribonucleoprotein (FMRP), a key RNA-binding protein that regulates transcription, translation, and mRNA localization. The absence of FMRP results in profound translational dysregulation, impairing synaptic plasticity and disrupting neuronal circuits. While FMRP primarily functions as a translational repressor, its precise spatial and activity-dependent regulation in the brain remains poorly understood due to limitations of bulk and conventional transcriptomic methods. To address this critical gap, we will employ advanced spatial genomics technologies to construct the first high-resolution, single-cell map of translational regulation in the FXS mouse brain. In Aim 1, we will generate spatial transcriptomics and translatomics maps of FXS and control mouse brains using STARmap-PLUS and RIBOmap. These datasets will allow us to quantify the abundance and translation of FMRP-target mRNAs, non-targets, cell-type markers, and regional markers, revealing how loss of FMRP alters mRNA localization and translation at brain-region- and cell- type-specific levels. In Aim 2, we will investigate how synaptic activity modulates spatial mRNA translation by inducing activity-dependent long-term depression (LTD) in brain slices using a well-established protocol. This approach will provide the first direct link between synaptic stimulation and localized mRNA translation dynamics in FXS, offering novel insights into how synaptic dysfunction contributes to disease pathology. This study represents a significant technical and conceptual advance in FXS research, offering an unprecedented spatially resolved view of FMRP-mediated regulation at single-cell and subcellular levels. By uncovering activity- dependent translational dysregulation in FXS, our findings will generate critical mechanistic insights and inform novel therapeutic strategies targeting dysregulated local translation in neurodevelopmental disorders.