Grant: Project Grant

We study the cell biology of the genetic disorder Fragile X Syndrome (FXS), a leading cause of autism spectrum disorder. The primary factor underlying FXS is the loss of expression of FMRP, a single class of protein important to translation and function of at least 1000 other proteins. We are testing the effects that a loss of FMRP has on cell functions, and reintroducing portions of the FMRP molecule to restore activity, in a manner comparable to insulin treatment of diabetes. To do this, we attached the N-terminal region of FMRP to a "tat" peptide to make it capable of crossing the blood-brain barrier. When reintroduced by tail vein injection into a Fmr1 knockout (KO) mouse model of FXS, "N-tat" was rapidly taken up by neurons across the brain to restore protein translation, synaptic function, and hyperactivity for at least 24 hr without toxic effects (Zhan 2020). The current study will test the Hypothesis that a loss of FMRP in FXS induces change at the molecular to physiological levels which is normally prevented through select actions by structural domains located on the FMRP N- and C-termini. We are experts in electrophysiology (R Turner), with collaborative input from an expert in spatial transcriptomics/bioinformatics (S Morrissy). We will define how a loss of FMRP disrupts EEG as a final readout of cortical function (Aim 1), ion channel physiology (Aim 2), and RNA levels (Aim 3). Preliminary data reveal that N-tat and C-tat peptides exert restorative actions on ion channels at the level of the membrane to the levels of RNA that ultimately rescue cortical EEG for at least 3 days after a single injection. This project will be significant in identifying how a loss of FMRP affects multiple aspects of cell biology in Fragile X Syndrome, and will test a potential therapeutic strategy to reverse symptoms of this genetic disorder.