 My name is Daman Kumari. I'm a staff scientist at NIDDK. And my name is Kristen Malton. I'm a postdoc research fellow at the National Institute of Mental Health. We are going to introduce our recent study published in Human Rotation. This study was a collaboration among our labs at the NIH, the Center for Neural Science, New York State Institute for Basic Research in Developmental Disabilities, and the National Human Neural Stem Cell Results. Fretel X syndrome is the most common cause of inherited intellectual disability and autism. Expansion of a CGG repeat sequence in the 5-prime untranslated region of the FMR1 gene to more than 200 repeats causes transcriptional gene silencing and loss of its protein product FMRP. Axis of FMRP leads to the symptoms of Fretel X syndrome. The FMR1 knockout mass model for Fretel X syndrome has been useful in dissecting the molecular mechanisms responsible for disease pathology. This research has led to the development of targeted therapeutic approaches that reverse disease phenotype in FMR1 knockout mice. Our goal was to study if the molecular phenotypes seen in FMR1 knockout mice also occurred in primary human fibroblasts derived from Fretel X syndrome patients. For this, we studied two specific features of the disease seen in knockout mice, rates of protein synthesis, and the levels of signaling proteins that regulate it. Previous studies have shown that in the absence of FMRP, rates of cerebral protein synthesis are elevated in some brain regions of FMR1 knockout mice. These images illustrate the elevated rate of protein synthesis in the dorsal hippocampus of an FMR1 knockout mouse compared to that of a wild type. In that present study, we measured the rate of loosening cooperation into protein as an indicator of the basal rates of protein synthesis in human fibroblasts. We show that the average incorporation rate is significantly higher in fragile X syndrome fibroblasts compared to that of healthy controls. Next, we evaluated the phosphorylation states of key translational control molecules that have been shown to be dysregulated in studies of FMR1 knockout mice and other patient-derived samples. We found increased levels of phosphorylated mTOR, phosphorylated ERC12, and phosphorylated P70S6K1 in fragile X syndrome fibroblasts. We further explored the effect of small molecule inhibitors on loosening cooperation rates in human fibroblasts. We tested two selective inhibitors, first PF4708671, a drug that inhibits S6K1, which is a downstream target of mTORC1 and ERC, as well as TGX221, which inhibits P110β subunit of PI3K, which is a known FMRP target. Treatment with both inhibitors decreased rates of protein synthesis in human fibroblasts. Our data suggests that human fibroblasts can be used to screen and test potential therapeutic compounds before they are used in clinical trials. We encourage you to read the full manuscript for more information and email us with any questions. Happy reading!