Non-coding Functions of FMR1 Transcript in Metabolic Regulation of Human Neurons

Messenger RNAs are generally studied through the functions of their encoded proteins and their non-coding functions are largely ignored. Here, we show an unexpected dual-function role of the FMR1 transcript serving both protein-dependent and -independent functions in human neurodevelopment. A loss of FMR1 and its protein product fragile X messenger ribonucleoprotein (FMRP) leads to the neurodevelopmental disorder fragile X syndrome (FXS). FXS patients derived neurons display hyperexcitability and immature morphology, whereas FMRP knockout (FMRP-KO) neurons that retain FMR1 transcript expression do not. Multiomics analysis reveals key metabolic differences between FXS and FMRP-KO neurons. While both FXS and FMRP-KO neurons have reduced mitochondrial respiration, only FXS neurons exhibit elevated glycolysis. We discovered that the FMR1 transcript regulates the levels of glycolytic enzyme LDHA by inhibiting its binding to insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Finally, FMR1 transcript that does not translate FMRP rescued glycolytic and cellular deficits of FXS neurons. Therefore, our results suggest that FMR1 serves as a dual-function RNA in human neurodevelopment.