FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism

Shah, Sneha; Molinaro, Gemma; Liu, Botao; Wang, Ruijia; Huber, Kimberly M.; Richter, Joel D.

doi:10.1016/j.celrep.2020.02.076

Cited by 72 publications

(63 citation statements)

References 91 publications

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“…As a result, the expression of the gene is impaired, and either partial or complete silencing of FMRP occurs 7 . FMRP is an RNA-binding protein 8 that regulates different steps of mRNA metabolism 9 – 14 and binds only a fraction of mRNAs expressed in the brain 15 . A primary role of FMRP in the brain is the control of synaptic plasticity by regulating mRNA metabolism and repressing protein synthesis in dendrites and synapses 12 , 13 , 16 , 17 , and thereby its lack results in excessive protein synthesis 18 .…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice

et al. 2021

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In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A2A receptors (A2ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A2ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A2AR antagonist ZM241385 and strongly potentiated by the A2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A2AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A2AR-related downstream targets.

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Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice

et al. 2021

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“…Therefore, decreased RPF and TE may not always indicate reduced synthesis of protein. Some evidence indicates that FMRP stalls or slows ribosome translocation, and mGluR stimulation regulates translation elongation through FMRP and eEF2 phosphorylation [18,59,76,77]. Thus, for some mRNAs, the observed decrease in RPF or TE on FMRP target mRNAs in response to DHPG may be a consequence of enhanced ribosome movement that reflects increased protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…b ECDF of RNA (left), RPF (middle), and TE (right) expression changes in Fmr1 −/y /WT (log2FC) of FMRP targets compared to nontarget mRNAs. Data of hippocampal slices of Fmr1 −/y mice from Shah et al [ 76 ]. Wilcoxon rank-sum test with correction by Bonferroni method.…”

Section: Methodsmentioning

confidence: 99%

Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP

et al. 2020

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Background Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown. Methods We utilized Tsc2+/− mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2+/− and following mGluR-LTD synaptic plasticity. Results Ribosome profiling reveals that in Tsc2+/− mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1−/y hippocampi. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady-state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice. Conclusion These results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/− mice.

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“…Das Sharma et al, 2019;Shah et al, 2020 Neurodegenerative diseases TRAP method targeting cell types defined by genetics or projections can effectively profile translation regulation on memory consolidation associated with Alzheimer's disease. Accurately interference with the translation mechanism in specific cells of targeted regions may be a novel therapeutic target for neurodegenerative diseases.…”

Section: Elements Conclusion Referencesmentioning

confidence: 99%

“…In order to distinguish between transiting and stalled ribosomes, a modified procedure was used. After blocking initiation of all hippocampal-cortical slices, followed by translocation inhibition at different time points using cycloheximide, ribosome profiling was then used for sample analysis ( Shah et al, 2020 ). This approach detects mRNA-specific ribosome translocation dynamics in the nervous system, which is a remarkable breakthrough.…”

Section: Narrow Sense Translatomicsmentioning

confidence: 99%

Insights Into Translatomics in the Nervous System

et al. 2020

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Most neurological disorders are caused by abnormal gene translation. Generally, dysregulation of elements involved in the translational process disrupts homeostasis in neurons and neuroglia. Better understanding of how the gene translation process occurs requires detailed analysis of transcriptomic and proteomic profile data. However, a lack of strictly direct correlations between mRNA and protein levels limits translational investigation by combining transcriptomic and proteomic profiling. The much better correlation between proteins and translated mRNAs than total mRNAs in abundance and insufficiently sensitive proteomics approach promote the requirement of advances in translatomics technology. Translatomics which capture and sequence the mRNAs associated with ribosomes has been effective in identifying translational changes by genetics or projections, ribosome stalling, local translation, and transcript isoforms in the nervous system. Here, we place emphasis on the main three translatomics methods currently used to profile mRNAs attached to ribosome-nascent chain complex (RNC-mRNA). Their prominent applications in neurological diseases including glioma, neuropathic pain, depression, fragile X syndrome (FXS), neurodegenerative disorders are outlined. The content reviewed here expands our understanding on the contributions of aberrant translation to neurological disease development.

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FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism

Cited by 72 publications

References 91 publications

Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice

Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice

Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP

Insights Into Translatomics in the Nervous System

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