Metabotropic Glutamate Receptor Activation Regulates Fragile X Mental Retardation Protein and<i>Fmr1</i>mRNA Localization Differentially in Dendrites and at Synapses

Antar, Laura N.; Afroz, Rownak; Dictenberg, Jason B.; Carroll, Reed C.; Bassell, Gary J.

doi:10.1523/jneurosci.0099-04.2004

Cited by 352 publications

(369 citation statements)

References 37 publications

(51 reference statements)

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“…Only then it will be possible to tie the current results into the broader picture of autism pathogenesis, also because, despite its intended adaptive value, the decrease in PRKCB1 gene expression recorded in most autistic brains could still play a negative role, for example by blocking the physiological relocation of both FMRP and Fmr1 mRNA in dendrites following activation of metabotropic glutamate receptors. 59 The significant association recorded here between PRKCB1 gene variants and enhanced urinary peptide excretion rates increases confidence in the reliability of our results and spurs further interest in the underlying pathophysiology. Functional PRKCB1 promoter variants have been shown to be associated with diabetic nephropathy and albuminuria, 60,61 mediated by increased renal oxidative stress, production of fibrotic cytokines such as TGFb, and consequently increased glomerular permeability.…”

supporting

confidence: 67%

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

et al. 2008

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Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and bII isoenzymes result from the alternative splicing of the PKCb gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P < 0.05) and have the autistic endophenotype of enhanced oligopeptiduria (P < 0.05). Temporocortical PRKCB1 gene expression was reduced on average by 35 and 31% for the PRKCB1-1 and PRKCB1-2 isoforms (P < 0.01 and < 0.05, respectively) according to qPCR. Protein amounts measured for the PKCbII isoform were similarly decreased by 35% (P = 0.05). Decreased gene expression characterized patients carrying the 'normal' PRKCB1 alleles, whereas patients homozygous for the autism-associated alleles displayed mRNA levels comparable to those of controls. Whole genome expression analysis unveiled a partial disruption in the coordinated expression of PKCb-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCb roles in altered epithelial permeability, demonstrate a significant downregulation of brain PRKCB1 gene expression in autism and suggest that it could represent a compensatory adjustment aimed at limiting an ongoing dysreactive immune process. Altogether, these data underscore potential PKCb roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability.

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supporting

confidence: 67%

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

et al. 2008

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“…FMRP binds and is involved in transport of RNA to synapses, where it also regulates translation (for review, see Antar and Bassell, 2003). FMRP is critically involved in synaptic plasticity, acting downstream of group I metabo-tropic glutamate receptors to regulate synapse-specific RNA translocation and translation (Antar et al, 2004(Antar et al, ,2005Bear et al, 2004;Weiler et al, 2004;Aschrafi et al, 2005). We have demonstrated here that stau is expressed by neurons in the DRG and TG of the rat and in the human TG.…”

mentioning

confidence: 66%

The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons

et al. 2006

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Neuronal proteins have been traditionally viewed as being derived solely from the soma; however, accumulating evidence indicates that dendritic and axonal sites are capable of a more autonomous role in terms of new protein synthesis. Such extra-somal translation allows for more rapid, on-demand regulation of neuronal structure and function than would otherwise be possible. While mechanisms of dendritic RNA transport have been elucidated, it remains unclear how RNA is trafficked into the axon for this purpose. Primary afferent neurons of the dorsal root (DRG) and trigeminal (TG) ganglia have among the longest axons in the neuraxis and such axonal protein synthesis would be advantageous, given the greater time involved for protein trafficking to occur via axonal transport. Therefore, we hypothesized that these primary sensory neurons might express proteins involved in RNA transport. Rat DRG and TG neurons expressed staufen (stau) 1 and 2 (detected at the mRNA level) and stau2 and fragile × mental retardation protein (FMRP; detected at the protein level). Stau2 mRNA was also detected in human TG neurons. Stau2 and FMRP protein were localized to the sciatic nerve and dorsal roots by immunohistochemistry and to dorsal roots by Western blot. Stau2 and FMRP immunoreactivities colocalized with transient receptor potential channel type 1 immunoreactivity in sensory axons of the sciatic nerve and dorsal root, suggesting that these proteins are being transported into the peripheral and central terminals of nociceptive sensory axons. Based on these findings, we propose that stau2 and FMRP proteins are attractive candidates to subserve RNA transport in sensory neurons, linking somal transcriptional events to axonal translation. Keywordsprimary afferent neuron; fragile X mental retardation protein; staufen; RNA binding protein; axonal translation; RNA cargoThe discovery that RNA is transported to synaptic sites by RNA transport proteins, where it can be translated on demand, has provided insight into how neurons handle the rapid synaptic architectural and signaling changes that are known to occur in brain areas associated with learning and memory (Job and Eberwine, 2001;Steward and Worley, 2002;Steward and Schuman, 2003;Martin, 2004;Tiedge, 2005). There is now compelling evidence that translation occurs in axons (Koenig, 1967;Nixon, 1980;Koenig, 1991;Eng et al., 1999;Brittis et al., 2002;Piper and Holt, 2004), as mRNA and translational machinery have been localized to CNS (Tiedge et al., 1993;Aronov et al., 2001;Brittis et al., 2002), sympathetic (Olink-Coux andHollenbeck, 1996;Eng et al., 1999) and sensory (Zheng et al., 2001;Li et al., 2004a;Verma et al., 2005;Willis et al., 2005) axons. Moreover, an emerging physiological role for local translation in axons has been described for growth cone guidance and collapse (Zheng et al., 2001;Li et al., 2004a;Verma et al., 2005;Wu et al., 2005).Primary sensory neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG) have among the longest axons of the entire ne...

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“…FMRP interaction with miRNA machinery is closely associated with its role in regulating the translation of mRNAs housed in RNPs. 180,181 In cultured hippocampal neurons, neuronal activation results in disassembly of specific neuronal RNA granules concurrently with increased local translation of RNAs localized to these granules. Stimulation releases free mRNA as well as ribosomes indicative of derepression.…”

Section: Prion Like Domains In Neuronal Rnp Mediated Translationmentioning

confidence: 99%

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

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Metabotropic Glutamate Receptor Activation Regulates Fragile X Mental Retardation Protein andFmr1mRNA Localization Differentially in Dendrites and at Synapses

Cited by 352 publications

References 37 publications

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

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