Translational Control in the Brain in Health and Disease

Sossin, Wayne S.; Costa-Mattioli, Mauro

doi:10.1101/cshperspect.a032912

Cited by 107 publications

(92 citation statements)

References 161 publications

(194 reference statements)

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“…eIF2 phosphorylation suppresses general translation, but selectively stimulates the translation of these specific mRNAs, especially in response to certain external stimuli and cellular stresses. Control of protein translation is particularly important for synaptic plasticity underlying memory formation 42 . Many neuron-specific genes also have long 5′UTR with multiple short uORF and are regulated in same way by eIF2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Translational Inhibition of α-Neurexin 2

Ding

Meng

Zhou

et al. 2020

Sci Rep

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Neurexins are extensively investigated presynaptic cell-adhesion molecules which play important roles in transmitting signals and processing information at synapses that connect neurons into a vast network of cellular communications. Synaptic transmission of information is a fast and dynamic process which relies on rapid and tight regulation of synaptic protein expression. However, the mechanism underlying those regulation is still not fully understood. Therefore, we explore how the expression of NRXN2α, one of encoding genes for neurexins, is regulated at the translational level. NRXN2α transcript has a long and conserved 5′-untranslated region (5′UtR) suggestive of the rapid regulation of protein expression at the translational level. We first demonstrate that the 5′UTR has negative effects on the expression of the NRXN2α and find a critical subregion responsible for the major inhibitory function. Then we identify a particular secondary structure of G-quadruplex in the 5′UTR. Moreover, we find that the synergistic roles of G-quadruplex and upstream AUGs are responsible for most of NRXN2α-5′UTR inhibitory effects. In conclusion, we uncovered 5′ UTR of neurexin2 potentially inhibits neurexin2 translation by multiple mechanisms. In addition, this study underscores the importance of direct protein quantitation in experiments rather than using mRNA as an indirect estimate of protein expression.

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Section: Discussionmentioning

confidence: 99%

Translational Inhibition of α-Neurexin 2

Ding

Meng

Zhou

et al. 2020

Sci Rep

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“…Once localized to the synapse these mRNAs are likely maintained in a translationally repressed state during the stage of elongation until suitable synaptic signals release this repression [241][242][243][244][245][246][247][248] . This has been suggested to be a common mechanism regulating protein synthesis in neuronal processes 35,[249][250][251] .…”

Section: A Seventh Common Upstream Regulatory Pathway Dmd (Dystrophimentioning

confidence: 99%

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Driesche

Sawicka

Zhang

et al. 2019

Preprint

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Highlights 1. We have created a mouse model in which endogenous FMRP can be conditionally tagged.2. Using tag-specific CLIP we describe ranked and specific sets of in vivo FMRP mRNA targets in two types of neurons.3. This ranking was used to reveal that FMRP regulates mRNAs with long coding sequences.4. FMRP mRNA targets in Purkinje cells, including the top-ranked IP3 receptor, are related to cell-autonomous Fragile X phenotypes. 5.We have updated our previous list of whole mouse brain FMRP mRNA targets with more replicates, deeper sequencing and improved analysis 6. The use of tagged FMRP in less abundant cell populations allowed identification of novel mRNA targets missed in a whole brain analysis

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“…In brain and at synapses, several converging lines of evidence suggest that translational repression occurs mainly at the level of initiation (Sossin and Costa-Mattioli, 2018), halting assembly of the pre-initiation complex containing the small ribosomal subunits. The efficiency of mRNA translation is regulated through phosphorylation of translation initiation factors such as eIF4E or the eIF4E-binding proteins (4E-BPs).…”

Section: Fmrp Lost In Synaptic Translationmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

267

258

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Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. ASDs and FXS: Causes and Clinical Features Approximately 1%-3% of the general population is affected by intellectual disabilities (IDs). IDs are neurodevelopmental disorders defined by significant limitations in intellectual functioning and adaptive behaviors and often exhibit comorbidity with autism (Mefford et al., 2012). Autism spectrum disorders (ASDs) are characterized by high phenotypic heterogeneity, comprising deficits in social interaction and communication as well as repetitive and stereotyped behaviors (

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Translational Control in the Brain in Health and Disease

Cited by 107 publications

References 161 publications

Translational Inhibition of α-Neurexin 2

Translational Inhibition of α-Neurexin 2

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

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