Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

Ferron, Laurent; Nieto-Rostro, Manuela; Cassidy, John S.; Dolphin, Annette C.

doi:10.1038/ncomms4628

Cited by 124 publications

(158 citation statements)

References 55 publications

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“…One intriguing possibility is that FXGs are associated with ion channels, since FMRP directly binds to ion channels and modulates their function in axons (11,(44)(45)(46). These findings suggest a model in which FXGs constitutively associate with channels while mRNAs transition between FXG and non-FXG complexes in response to signalling events.…”

Section: Dynamic Association Of Rna With Fxgsmentioning

confidence: 87%

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

et al. 2017

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Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXGassociated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life.

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Section: Dynamic Association Of Rna With Fxgsmentioning

confidence: 87%

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

et al. 2017

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“…the N-type voltage-gated calcium channel, Ca v 2.2, to control its surface expression (25). FMRP also modulates activity of the large-conductance calcium-activated potassium (BK) channel in hippocampal and cortical excitatory neurons, which is critical for controlling action potential (AP) duration and neurotransmitter release (18).…”

mentioning

confidence: 99%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

132

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Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre-and postsynaptic defects, yet whether the pre-and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic-and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

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“…We first showed that neurons treated with FMRP had enhanced expression of N-type Ca 2+ channels as expected from the findings of Ferron et al 202 and with age, there was a reduction in the expression of these channels (Fig. 1a-b) (Here, we will refer to neurons treated with FMRP as neurons with elevated expression of N-type Ca 2+ channels ).…”

Section: Calcium Dye Incubation and Magnetic Force Stimulationmentioning

confidence: 57%

“…201 The fragile X mental retardation protein (FMRP) increases the density of N-type Ca 2+ channels, causing hyper-excitability. 202 The disease is also characterized by a deficiency of GABA receptors at the cortices of Fragile X mice, 203 contributing to epilepsy. 204 We hypothesized that if our magnetic platform could activate excitatory N-type Ca 2+ channels chronically, the neural networks might compensate by reducing the expression of these channels and increasing the expression of inhibitory ion channels/receptors.…”

Section: Calcium Dye Incubation and Magnetic Force Stimulationmentioning

confidence: 99%

Acute and Chronic Neural Stimulation via Mechano-Sensitive Ion Channels

Tay

2018

Springer Theses

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Neural stimulation techniques for eliciting calcium influx can elucidate the physiological roles of specific neural populations. To overcome some of the limitations of existing techniques such as poor specificity and noxious effects of heat, I developed a technology for non-invasive control of neural activities using magnetic forces and magnetic nanoparticles (MNPs) which offer deep tissue penetration and controllable dosage. Extensive investigations with different neurotoxins and experimental conditions support that the mechanism of magnetic stimulation that involves membrane-bound MNPs transducing magnetic forces into mechanical stretching of the cell membrane to enhance the opening probability of mechano-sensitive N-type calcium ion channels to induce calcium influx.Making use of the ability of neural networks to actively regulate their ratio of excitatory to inhibitory ion channel/receptor, I also performed chronic magnetic stimulation on fragile X iii syndrome (FXS) model neural networks. We found that chronic magnetic stimulation reduced the density of N-type calcium ion channels whose expression is increased in FXS. This technique demonstrates the potential of using bio-magnetic/mechanical forces to modulate expressions of mechano-sensitive ion channels where they are over-expressed in diseases such as abnormal nociception.Nonetheless, there are still a few areas where the technique can be improved. Firstly, it is the use of MNPs with more uniform properties to have greater control on magnetic stimulations.Secondly, the technique needs to be useful for in vivo studies. Therefore, I started researching on magnetotactic bacteria (MTB) which produce biological MNPs with superior properties such as uniform sizes and highly homogenous magnetic properties with the goal of harvesting MNPs from them.MTB, however, grow extremely slowly and the number of MNPs produced/bacterium is low. One way to overcome this problem is to evolve MTB over-producers of MNPs but this strategy is constrained by the absence of a selection platform that is quantitative and offer high throughput. To overcome this problem, I combined random chemical mutagenesis and selection using a magnetic ratcheting platform to generate and isolate MTB over-producers that produce twice as many MNPs/bacterium after 5 rounds of mutation/selection. I next designed a magnetic microfluidic device and demonstrate as a proof of concept, that it can be coupled to a bioreactor for high throughput microfluidic selection of MTB over-producers.iv

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Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

Cited by 124 publications

References 55 publications

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Acute and Chronic Neural Stimulation via Mechano-Sensitive Ion Channels

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