2012 Fragile X and Autism-Related Disorders: From Basic Neuroscience to Improved

Gordon Research Conferences, East Greenwich RI

Investigators

Abstract

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited intellectual deficiency and the most common identifiable single gene cause of autism, affecting 1 in 5,000 males and a lesser number of females. Autism spectrum disorders (ASD) occur in up to 2/3 of males and 1/3 of females with FXS. The Fragile X gene (FMR1) was cloned in 1991 and since then a large field has grown with over one hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMR1 gene homologs have been found in Drosophila and mice, and useful null mutant models generated in both. FMRP has been found to be involved in the regulation of specific messenger RNA transport, localization and expression in neurons. Briefly put, FMRP is thought to bind and help transport a crucial subset of messages to the sites of neural action (the synapses). At those synapses, FMRP is a critical switch that mediates changes in local protein expression in response to neural activity - in effect causing the synapses to strengthen or weaken as required in response to experience. When FMRP is reduced or missing in an affected person, the synapses are much less able to change with experience and learning is greatly reduced. More recently, specific signaling mechanisms have been proposed to mediate this control at the synapse, via a specific set of Gq-linked neurotransmitter receptors, including group I mGluRs (metabotropic glutamate receptors). In addition to clinical overlap between FXS and ASD, there is substantial overlap in the molecular pathology of the two disorders. Molecular defects known to cause ASD may involve proteins in signaling pathways that regulate FMRP activity, proteins for which synaptic translation is regulated by FMRP, or defects in neurotransmitter systems shown to be dysregulated in FXS models. Molecules aimed at targets in pathways that are dysregulated in the absence of FMRP are now being developed and tested in academic laboratories and through the pharmaceutical industry, in order to offer effective drug therapies targeted to the underlying neural pathology fo patients with FXS. It is expected that many such treatments will have therapeutic overlap in subsets of individuals with ASD. This conference will bring together leading scientists and clinicians in the Fragile X and ASD fields, particularly those working on forms of ASD with lesions in molecular pathways that overlap those implicated in FXS. Topics will include molecular pathways, synaptic signaling and function, targeted treatment in model systems, outcome measures, and translation to small molecule treatment trials in humans with FXS. The conference is expected to accelerate the pace of bench-to-bedside translational research to bring important targeted treatments to individuals with FXS and autism. PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FXS) is the most common known single gene cause of intellectual disability and autistic spectrum disorder (ASD). In the past 20 years since discovery of FMR1, the fragile X gene, tremendous progress has been made toward understanding mechanisms of neural dysfunction in FXS and it is now clear these mechanisms overlap with those active in a subset of ASD. This conference will together basic scientists and clinical researchers in the FXS and ASD field with a goal of accelerating translation of new neuroscience and molecular findings to treatments targeting the underlying disorder for both FXS and ASD.