Our previous work focused on the molecular
mechanisms underlying dysregulated synaptic protein synthesis, signal
transduction and hyperexcitability in fragile X syndrome (FXS), an inherited
intellectual disability and autism spectrum disorder. We have shown
that the fragile X mental retardation protein (FMRP) regulates synaptic expression and enzymatic activity of the
intracellular signaling complex, phosphoinositide-3 kinase (PI3K), leading to
excess PI3K signaling in Fmr1 knockout
mice (Gross et al., 2010). FMRP directly controls the mRNA translation and
expression of at least two components of this pathway, the PI3K catalytic
subunit p110β, and the PI3K enhancer PIKE, suggesting them as potential
therapeutic targets for FXS and other autism spectrum disorders. In a subsequent
study, we showed that excess and dysregulated protein synthesis in lymphoblastoid
cell lines from patients with FXS could be rescued by a p110β subunit-selective
inhibitor, pointing towards a novel therapeutic strategy for FXS (Gross and
Bassell, 2012). We are currently following up on these findings using genetic
and pharmacological methods.
FMRP directly regulates expression of
the PI3K pathway components p110β (1) and PIKE (2), leading to enhanced and
dysregulated PI3K signaling downstream of metabotropic glutamate receptors 1
and 5, but also of other G-protein coupled receptors (GPCRs), as well as GABA
receptors, receptor tyrosine kinases (RTKs) and cytokine receptors.