Balancing Arc Synthesis, mRNA Decay, and Proteasomal Degradation

Soulé, Jonathan; Alme, Maria Nordheim; Myrum, Craig; Schubert, Manja; Kanhema, Tambudzai; Bramham, Clive R.

doi:10.1074/jbc.m112.376491

Cited by 63 publications

(41 citation statements)

References 86 publications

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“…TDD degrades transcripts after a single round of translation, thereby tightly regulating associated protein levels (Maquat et al, 2011). Additionally, ARC protein turns over quickly and thus has a relatively short half-life, in some cases as short as 37 minutes (Rao et al, 2006; Messaoudi et al, 2007; Soule et al, 2012). It has also been shown that local Arc mRNA level is highly predictive of ARC protein level in vivo when induced by either learning or LTP (Farris et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…Arc mRNA is degraded by TDD mechanisms following only a few rounds of translation (Giorgi et al, 2007), and ARC protein has a relatively short half-life of 37 minutes (Soule et al, 2012), accounting for the tight correspondence between RNA and protein. Given that behavioral training in aged impaired rats failed to induce the Arc transcription observed in the young and AU hippocampus, we expected that ARC protein levels would also be lower in AI rats.…”

Section: Discussionmentioning

confidence: 99%

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A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging

Fletcher

Hill

Long

et al. 2014

Neurobiology of Learning and Memory

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Memory decline is a common feature of aging. Expression of the immediate-early gene Arc is necessary for normal long-term memory, and although experience dependent Arc transcription is reportedly reduced in the aged rat hippocampus, it has not been clear whether this effect is an invariant consequence of growing older, or a finding linked specifically to age-related memory impairment. Here we show that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. While these findings are consistent with the possibility that blunted Arc transcription contributes to cognitive aging, we also found increased basal ARC protein levels in the CA1 field of the hippocampus in aged rats with memory impairment, together with a loss of the experience dependent increase observed in young and unimpaired aged rats. Follow-up analysis revealed that increased basal translation and blunted ubiquitin mediated degradation may contribute to increased basal ARC protein levels noted in memory impaired aged rats. These findings indicate that Arc expression is regulated at multiple levels, and that several of these mechanisms are altered in cognitively impaired aged rats. Defining the influence of these alterations on the spatial and temporal fidelity of synapse specific, memory-related plasticity in the aged hippocampus is an important challenge.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging

Fletcher

Hill

Long

et al. 2014

Neurobiology of Learning and Memory

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“…The exon-junction complex (EJC) is critical to global mRNA function (Tange et al, 2004), with a role mediating neuronal Arc mRNA expression recently coming to light (Giorgi et al, 2007). One postulated mechanism regulating Arc mRNA availability is translation dependent decay (TDD) through the RNA surveillance process of nonsense-mediated mRNA decay (NMD) (Giorgi et al, 2007, Soule et al, 2012), wherein mRNAs can be degraded following the first round of translation if EJCs remain bound to the transcript (Maquat, 2004). Arc mRNA is a natural target for TDD due to the two EJCs within the 3’UTR, theoretically leading to tight control of Arc mRNA availability and protein synthesis (Giorgi et al, 2007).…”

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confidence: 99%

Expression of the core exon-junction complex factor eukaryotic initiation factor 4A3 is increased during spatial exploration and striatally-mediated learning

2012

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Regulation of dendritically localized mRNAs offers an important means by which neurons can sculpt precise signals at synapses. Arc is one such dendritically localized mRNA, and it has been shown to contain two exon-junction complexes (EJC) within its 3’UTR. The EJC has been postulated to regulate cytoplasmic Arc mRNA availability through translation dependent decay and thus contribute to synaptic plasticity. Core proteins of the EJC include eIF4A3, an RNA helicase, and Magoh, which stabilizes the interaction of eIF4A3 with target mRNAs. Arc mRNA expression is activity-regulated in numerous brain regions, including the dorsal striatum and hippocampus. Therefore in this study, the in vivo expression of these core EJC components was investigated in adult Sprague-Dawley rats to determine whether there are also behaviorally-regulated changes in their expression. In the present work, there was no change in the expression of Magoh mRNA following spatial exploration, a paradigm previously reported to robustly and reliably upregulate Arc mRNA expression. Interestingly, however, there were increases in eIF4A3 mRNA levels in dorsal striatum and hippocampus following spatial exploration, similar to previous reports for Arc mRNA. Furthermore, there were activity-dependent changes in eIF4A3 protein distribution and expression within striatum following spatial exploration. Importantly, eIF4A3 protein colocalized with Arc mRNA in vivo. Like Arc mRNA expression, eIF4A3 mRNA expression in dorsomedial striatum, but not dorsolateral striatum or hippocampus, significantly correlated with behavioral performance on a striatally-mediated, response-reversal learning task. This study provides direct evidence that a core EJC component, eIF4A3, shows activity-dependent changes in both mRNA and protein expression in the adult mammalian brain. These findings thus further implicate eIF4A3 as a key mediator of Arc mRNA availability underlying learning and memory processes in vivo.

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“…The lack of effect that VPA had on Arc could be inherent to SH-SY5Y cells. Past studies found that Arc expression in these cells is a fine-tuned balancing act between translation-dependent mRNA decay and proteasomal degradation and without specific stimulation Arc expression is negligible (Soulé et al, 2012). This leads us to consider that regulation of Arc may not be so dependent on histone acetylation, thus, VPA may not act on the chromatin in the promoter region of Arc the same way as with KAT6B and APP.…”

Section: Resultsmentioning

confidence: 99%

Novel method to ascertain chromatin accessibility at specific genomic loci from frozen brain homogenates and laser capture microdissected defined cells

et al. 2016

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We describe a novel method for assessing the “open” or “closed” state of chromatin at selected locations within the genome. This method combines the use of Benzonase, which can digest DNA in the presence of actin, with qPCR to define digested regions. We demonstrate the application of this method in brain homogenates and laser captured cells. We also demonstrate application to selected sites within more than one gene and multiple sites within one gene. We demonstrate the validity of the method by treating cells with valproate, known to render chromatin more permissive, and by comparison with classical digestion with DNase I in an in vitro preparation. Although we demonstrate the use of this method in brain tissue we also recognize its applicability to other tissue types.

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Balancing Arc Synthesis, mRNA Decay, and Proteasomal Degradation

Cited by 63 publications

References 86 publications

A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging

A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging

Expression of the core exon-junction complex factor eukaryotic initiation factor 4A3 is increased during spatial exploration and striatally-mediated learning

Novel method to ascertain chromatin accessibility at specific genomic loci from frozen brain homogenates and laser capture microdissected defined cells

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