ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects

The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shrub mRNA (human Chmp4) to repress Shrub expression, causing overexpression during the disease state early-use critical period. The FXS hallmark is synaptic overelaboration causing circuit hyperconnectivity. Testing innervation of a central brain learning/memory center, we found FMRP loss and Shrub overexpression similarly increase connectivity. The ESCRT-III core protein Shrub has a central role in endosome-to-multi-vesicular body membrane trafficking, with synaptic requirements resembling FMRP. Consistently, we found FMRP loss and Shrub overexpression similarly elevate endosomes and result in the arrested accumulation of enlarged intraluminal vesicles within synaptic boutons. Importantly, genetic correction of Shrub levels in the FXS model prevents synaptic membrane trafficking defects and strongly restores innervation. These results reveal a new molecular mechanism underpinning the FXS disease state.