Abstract
Fragile X syndrome (FXS) is the most frequent inherited cause of intellectual disability and the best-studied monogenic cause of autism. FXS results from the functional absence of the fragile X mental retardation protein (FMRP) leading to abnormal pruning and consequently to synaptic communication defects. Here we show that FMRP is a substrate of the small ubiquitin-like modifier (SUMO) pathway in the brain and identify its active SUMO sites. We unravel the functional consequences of FMRP sumoylation in neurons by combining molecular replacement strategy, biochemical reconstitution assays with advanced live-cell imaging. We first demonstrate that FMRP sumoylation is promoted by activation of metabotropic glutamate receptors. We then show that this increase in sumoylation controls the homomerization of FMRP within dendritic mRNA granules which, in turn, regulates spine elimination and maturation. Altogether, our findings reveal the sumoylation of FMRP as a critical activity-dependent regulatory mechanism of FMRP-mediated neuronal function.
Highlights
Fragile X syndrome (FXS) is the most frequent inherited cause of intellectual disability and the best-studied monogenic cause of autism
Here, we report for the first time that fragile X mental retardation protein (FMRP) is a sumoylation target in vivo
We identify three sumoylatable residues, two of which lay within the N-terminal domain of FMRP and are the active small ubiquitin-like modifier (SUMO) sites
Summary
Fragile X syndrome (FXS) is the most frequent inherited cause of intellectual disability and the best-studied monogenic cause of autism. FMRP binds a large subset of mRNAs in the mammalian brain and is a key component of RNA granules These granules transport mRNA along axons and dendrites and are targeted to the base of active synapses to regulate local translation in an activity-dependent manner[3,4,5]. According the role of FMRP in regulating translation at synapses, the loss of FMRP function in FXS leads to a patholological hyperabundance of long thin immature dendritic protrusions called filopodia[6,7] These structural defects result from an abnormal post-synaptic maturation and/or a failure in the synapse elimination process[8]. A deeper comprehension of the activity-dependent molecular mechanisms controlling FMRP is absolutely criticial to understanding the functional regulation of FMRP-mediated mRNA transport and local protein synthesis in physiological and pathological conditions, including FXS. Sumoylation influences various aspects of the neuronal function including neurotransmitter release[27,28], spinogenesis[29,30], and synaptic communication[31,32,33]
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