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Grant Report 2016

Grant Reports Archive

Principle Investigator:             Dr. Karun K. Singh Ph.D.
                                                  McMaster University, Stem Cell and
                                                  Cancer Research Institute

Post Doctoral Fellow:             Dr. Sean White Ph.D.
Amount:                                   $45,000
Start Date:                                September 1, 2016


The Role of TAO2 in Fragile X

The underlying genetic cause of Fragile-X syndrome (FXS) is due to a failure in the production of the fragile X mental retardation protein (FMRP), through the silencing of the Fmr1 gene. In neurons, FMRP acts as repressor of protein production and is known to influence neurotransmitter release and synaptic plasticity. When FMRP is missing, the result is often an increase in protein levels involved in a number of pathways involved in learning and memory. Since it has been shown that FMRP can bind at least 842 different targets in the brain, it is difficult to distinguish the effect of one protein with another. Considering the high prevalence of autism spectrum disorders in FXS patients, it is not surprising that a number of FMRP binding targets are also autism-linked genes. One of these FMRP targets, whose function that we explore in our lab, is the enzyme known asthousand and one amino acid kinase 2 (TAO2). By comparing the brain cell profile of FXS mice, with a mouse deficient in only a single target (TAO2 for example), we can connect novel molecular pathways that contribute to effects of the fragile X mutation on affected individuals.  The similarities between the two models revolve around the impaired brain cell branches (dendritic spine morphology), which is the main site of excitatory synaptic transmission, and its underlying molecular pathways. These dendritic spines normally have a group of receptors on their surface, which are known as the metabotropic glutamate receptors (mGluR). The disruption of this pathway is currently the focus of potential therapeutic interventions. We hope to explore a novel FMRP-TAO2 pathway to determine if it is dependent on the activation of mGluR receptors, or possibly affected through an alternative mechanism, which may be an ultimate target for possible drug discovery.

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