The FMR1 repeat as functional element and therapeutic target in Fragile X disorders. Short Tandem repeat (STR) expansions cause ~50 inherited neurological diseases. However, disease associated loci represent only a small fraction of the ~3 million STRs present in the human genome. Despite their importance in human disease, the broader question of what intrinsic roles these repetitive elements play in normal neurobiology is largely unexplored. We recently discovered a conserved and native function for CGG repeats in the 5’ UTR of FMR1. This repeat expands in Fragile X Syndrome (FXS, a common cause of autism and intellectual disability) and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS, an age related neurodegenerative disorder). At normal and expanded sizes, FMR1 CGG repeats trigger translation of multiple cryptic proteins in the absence of an AUG start codon (CGG RAN translation). We recently described how CGG repeats and RAN translation act as an upstream open reading frame (uORF) to impede translation of the fragile X protein, FMRP. Using a combination of reporter assays as well as RAN translation blocking antisense oligonucleotides (RAN ASOs) in human neurons, we found that both the CGG repeats and RAN translation inhibit FMRP synthesis basally. This inhibition is alleviated by metabotropic glutamate receptor (mGluR) activation, which underlies a form of synaptic plasticity important for learning and memory and implicated in Fragile X-associated disorders. Based on these findings, our central hypothesis is that RAN translation and tandem microsatellite repeats have native functions in the regulation of the genes in which they reside, and that aberrancies in these native functions contribute to human disease. Our goals in this project are 3 fold: 1) Determine the mechanisms by which CGG repeats and RAN translation regulate FMRP synthesis, 2) investigate what consequences result from disrupting this regulatory loop in both mouse models and human neurons, and 3) evaluate whether ASOs can be used to simultaneously suppress RAN translation and activate FMRP synthesis in FXS and FXTAS human neurons as a step towards novel therapeutic development.