Regulatory BC1 RNA and the Fragile X Mental Retardation Protein: Convergent Functionality in Brain

Zhong, Jun; Chuang, Shih-Chieh; Bianchi, R. M.; Zhao, Wangfa; Paul, Geet; Thakkar, Punam; Liu, David; Fenton, André A.; Wong, Robert K. S.; Tiedge, Henri

doi:10.1371/journal.pone.0015509

Cited by 41 publications

(61 citation statements)

References 52 publications

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“…Epileptogenic susceptibility to auditory stimuli was tested as described before (Zhong et al, 2009, 2010). Briefly, 20–22 day-old 3xTg-AD and WT mice were subjected to auditory stimulation for 5 min in a plastic cage with a high-pitched siren (120 dB) from a personal alarm device (TBO-Tech, Bonita Springs, FL, USA) mounted under a Styrofoam cage cover.…”

Section: Methodsmentioning

confidence: 99%

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

Kazim

Chuang

Zhao

et al. 2017

Front. Aging Neurosci.

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Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer’s disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~3 weeks of age [prior to amyloid beta (Aβ) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human Aβ precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aβ expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes Aβ plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/Aβ antibody and by mGluR5 blockade in 3xTg-AD mice.

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Section: Methodsmentioning

confidence: 99%

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

Kazim

Chuang

Zhao

et al. 2017

Front. Aging Neurosci.

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“…Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47,48). These phenotypical manifestations are consonant with the molecular role of BC RNAs as translational repressors.…”

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confidence: 88%

“…Translational control mediated by BC1 RNA is important in the management of neuronal excitability (8,47,48). Lack of BC1 RNA in a BC1…”

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confidence: 99%

Dual Nature of Translational Control by Regulatory BC RNAs

Eom

Berardi

Zhong

et al. 2011

Molecular and Cellular Biology

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In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3 stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems.Translational control is an important means for the regulation of gene expression in eukaryotic cells (22). In neurons, the local translation of select mRNAs in synaptodendritic domains is considered a key determinant of neuronal function and plasticity (11,13,28,42). Strict control of local translation is essential to ensure that relevant proteins are synthesized only when and where needed (11). Progress has been made over the last 10 years as translational control mechanisms have been investigated in neurons, and several translational regulators have been identified (33,46). In one of these mechanisms, the effectors of neuronal translational control are regulatory BC RNAs (2,8,(43)(44)(45).Dendritic BC RNAs, neuronal small cytoplasmic RNAs (scRNAs) that include rodent BC1 RNA and primate BC200 RNA (20,21,40,41), are non-protein-coding RNAs that regulate translation at the level of initiation (43, 44). Translational control mediated by BC1 RNA is important in the management of neuronal excitability (8,47,48). Lack of BC1 RNA in a BC1Ϫ/Ϫ animal model triggers increased group I metabotropic glutamate receptor-dependent synthesis of select synaptic proteins (47). Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47, 48). These phenotypical manifestations are consonant with the molecular role of BC RNAs as translational repressors. BC1 RNA inhibits recruitment of the 43S preinitiation complex to the mRNA (44), a rate-limiting step in translation initiation that is mediated by the eIF4 family of eukaryotic initiation factors (6,9,12,31).The...

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“…In addition, FMRP was shown to restrict the synaptic synthesis of Arc/Arg3.1 and Map1b by interacting with the non-coding RNA, BC1 (Zalfa et al, 2003); however, there are contradicting reports regarding the interaction between FMRP and BC1 (Iacoangeli et al, 2008). A recent study suggests convergent regulation of FMRP and BC1 in neuronal function and excitability (Zhong et al, 2010). The association between FMRP and components of the microRNA pathway have encouraged studies of how FMRP and microRNAs work together to control translation (Ishizuka et al, 2002, Jin et al, 2004).…”

Section: Translational Regulation In Dendrites and At Synapsesmentioning

confidence: 99%

Dendritic protein synthesis in the normal and diseased brain

Swanger

Bassell

2013

Neuroscience

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Synaptic activity is a spatially-limited process that requires a precise, yet dynamic, complement of proteins within the synaptic micro-domain. The maintenance and regulation of these synaptic proteins is regulated, in part, by local mRNA translation in dendrites. Protein synthesis within the postsynaptic compartment allows neurons tight spatial and temporal control of synaptic protein expression, which is critical for proper functioning of synapses and neural circuits. In this review, we discuss the identity of proteins synthesized within dendrites, the receptor-mediated mechanisms regulating their synthesis, and the possible roles for these locally synthesized proteins. We also explore how our current understanding of dendritic protein synthesis in the hippocampus can be applied to new brain regions and to understanding the pathological mechanisms underlying varied neurological diseases.

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Regulatory BC1 RNA and the Fragile X Mental Retardation Protein: Convergent Functionality in Brain

Cited by 41 publications

References 52 publications

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

Dual Nature of Translational Control by Regulatory BC RNAs

Dendritic protein synthesis in the normal and diseased brain

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