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Abstract

Fragile X syndrome, which results from the loss of expression of the RNA binding protein FMRP (Fragile X Mental Retardation Protein), is a leading cause of intellectual disability and autism spectrum disorders.  In order to better understand the molecular perturbations of the Fragile X syndrome (FXS) we reasoned that one needed to identify FMRP target RNA in several brain regions at a developmental time point when FMRP expression peaks. We performed several molecular biology experiments and a thorough bioinformatics analysis to identify and group FMRP target mRNAs according to their functions, tissue expression and cellular origin. We also mapped FMRP binding sites on the target mRNA in order to gain further insights into how FMRP recognizes its RNA partners (1). Our analysis led us to further investigate one special mRNA target, Pde2a . Pde2a codes for a phosphodiesterase, an enzyme which degrades cAMP and cGMP, intracellular second messengers that play key roles in nervous system development and function. We could show that in the FXS mouse model, the Fmr1-KO mouse, PDE2A levels and activity are increased in several brain regions that are required for memory and cognition. Our results demonstrate that inhibiting PDE2A is a promising therapeutic approach for FXS, indeed blocking PDE2A activity reverses several FXS phenotypes in vitro, ex vivo and in vivo (2).

Bioinformatics also showed that calcium homeostasis could be regulated by FMRP. We used a microscopy approach to quantify calcium ion flux in FXS neurons. By showing that calcium ion homeostasis is deregulated in the absence of FMRP we identified a new cell phenotype that may be used in the future as a biomarker to help seek new drugs for FXS (3).

Last, I will present some recent and unpublished data on single cell transcriptomics analysis of FXS neurons and discuss how this powerful new technology can shed new lights on old results.

1. Maurin et al., Nucleic Acid Research, 2018
2. Maurin et al., Cerebral Cortex, 2018
3. Castagnola et al., Frontiers in Molecular Neuroscience, 2018