FMRP is an RNA-binding protein, and, despite its clear shuttling from the nucleus to the cytoplasm (59
), only the cytoplasmic function of FMRP has been well characterized. FMRP forms large cytoplasmic ribonucleoparticles containing several other proteins (61
) and RNAs (62
). FMRP has been detected in P bodies and stress granules as well, where it forms translationally silent preinitiation complexes (64
) (Figure ). FMRP regulates stability, subcellular transport, and translation of neuronal mRNAs encoding for proteins involved the in synaptic structure and function (58
). The best-characterized function of FMRP, based on studies of the Fmr1
KO mouse model (68
), is as a translational repressor (Figure ), and the absence of FMRP thus leads to increased protein synthesis (52
). High-throughput screenings supported by accompanying small scale studies have revealed that a wide array of neuronal mRNAs, with a large proportion encoding for presynaptic and postsynaptic proteins, is deregulated in the absence of FMRP, suggesting that concerted alteration of many proteins contributes to the FXS phenotype (62
Effects of receptor signaling pathways on FMRP-mediated regulation at synapses.
Spine dysmorphogenesis represents the quantitative measure widely adopted in the mouse model for FXS to understand cellular and network changes in the absence of FMRP (61
). Furthermore, extensive electrophysiological studies in the Fmr1
KO mouse model indicated an excitation/inhibition (glutamate/GABA; see below) imbalance (75
). Because the mouse model recapitulates morphological changes and behavioral deficits seen in human patients, these molecular insights have led clinicians to design targeted treatments (see below).
Over the last five years, there have been major advances in our understanding of the signaling pathways acting on FMRP as well as regulated by FMRP (Figure ). FMRP activity is regulated in response to metabotropic glutamate receptors (mGluRs) (78
), 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors (79
), γ-aminobutyric acid (GABA) receptors (76
-aspartate (NMDA) receptors (82
), and the tyrosine kinase or BDNF/NT-3 growth factor (TrkB) receptors (85
). Upon receptor activation, the FMRP-mediated translational block is released, possibly due to changes (86
) in its phosphorylation status, and protein synthesis can ensue. In the absence of FMRP, there is an increase in the synthesis of several proteins involved in cytoskeleton remodeling and receptor internalization (i.e., Arc) (Figure ) as well as reduction of other proteins due to a reduced stability of their mRNAs (i.e., GABA-R subunits). Elevation of the glutamate receptors mGluR1 and mGluR5 and the reduced insertion of AMPA receptors into the postsynaptic membrane are two of the central mechanics of impaired synaptic plasticity in FXS: such a dysregulated signaling is the basis of mGluR theory (75
). This receptor unbalance results in enhanced mGluR–long-term depression (mGluR-LTD), the most commonly studied forms of hippocampal synaptic plasticity.
The molecular signaling pathways orchestrating protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK (Figure ), are also impaired in FXS (72
), possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK (88