Molecular Bases Of The Fragile X Syndrome: Function Of Fmrp And Test Of A Novel Therapeutic Way In The Mouse Model
Reference : PhD Herve MOINE
Offer publication : April 6, 2016
Fragile X syndrome (FXS), the most frequent cause of inherited intellectual disability and autism, is caused by the absence of the RNA binding protein FMRP. The lack of FMRP causes an excessive translation of neuronal proteins associated with glutamatergic synapse maturation and function defects. Understanding how the lack of FMRP leads to synaptic alterations remains a major goal to define the molecular basis of FXS and identify a treatment.
We recently identified that FMRP mostly targets one unique mRNA in cortical neurons: the diacylglycerol kinase Dgkk that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. We showed that FMRP is necessary for Dgkk translation. The lack of FMRP abolishes group 1 metabotropic glutamate receptor-dependent Dgk activity in neurons, leading to excess of diacylglycerol and lack of
phosphatidic acid. Dgkk silencing in neurons causes dendritic spine abnormalities, synaptic plasticity alterations and behavior disorders similar to those observed in FXS mouse model. On the opposite, Dgkk overexpression in FXS neurons rescues spine alterations.
Altogether our results identify Dgkk as a major culprit in FXS physiopathology. Our results support a model where FMRP, by controlling the translation of a master-regulator kinase, controls the synaptic content of two key signaling lipids with impact on synaptic proteins expression and membrane properties. Our results set the basis for understanding FMRP function and testing novel therapeutic ways.
In this project, we will
1) define the molecular mechanism of FMRP translation control of Dgkk using gene reporter assays in neurons based on our CLIP data,
2) determine the functional consequences of Dgkk deregulation in mouse and human and demonstrate that its deregulation is critical for FXS condition with AAV-Dgk rescue experiments in mouse,
3) test a Dgk agonist (FDA approved) in the FXS mouse model that could represent a novel targeted mean to treat FXS.
- WISHED SKILLS : Solid bases in molecular biology required, knowledge in neuroscience would be a plus but is not mandatory
- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : Gene expression analysis techniques (qRT-PCR, WB, …), gene reporter system, ribosome profiling, CLIP-seq, primary neuron culture, RNA-protein interaction study, viral vector expression in neurons and mouse
Application Deadline : Dec. 31, 2016