Abstract
Localization of mRNAs to dendrites and local protein synthesis afford spatial and temporal regulation of gene expression and endow synapses with the capacity to autonomously alter their structure and function. Emerging evidence indicates that RNA binding proteins, ribosomes, translation factors and mRNAs encoding proteins critical to synaptic structure and function localize to neuronal processes. RNAs are transported into dendrites in a translationally quiescent state where they are activated by synaptic stimuli. Two RNA binding proteins that regulate dendritic RNA delivery and translational repression are cytoplasmic polyadenylation element binding protein and fragile X mental retardation protein (FMRP). The fragile X syndrome (FXS) is the most common known genetic cause of autism and is characterized by the loss of FMRP. Hallmark features of the FXS include dysregulation of spine morphogenesis and exaggerated metabotropic glutamate receptor-dependent long term depression, a cellular substrate of learning and memory. Current research focuses on mechanisms whereby mRNAs are transported in a translationally repressed state from soma to distal process and are activated at synaptic sites in response to synaptic signals.
Highlights
SYNAPTIC PLASTICITY Synaptic plasticity or long-lasting alterations in the efficacy of synaptic connections between two neurons has been proposed to be the cellular substrate of learning and memory (Malinow and Malenka, 2002; Bredt and Nicoll, 2003; Collingridge et al, 2004; Neves et al, 2008)
Persistent changes in synaptic efficacy are thought to involve at least two distinct phases – an early phase that is independent of new protein synthesis and a more long-lasting late phase that is dependent upon new protein synthesis (Bramham and Wells, 2007; Bramham, 2008; Richter and Klann, 2009)
The longterm activity-dependent increases of CaMKII and PSD-95, encoded by two mRNAs that are translationally repressed by fragile X mental retardation protein (FMRP) (Zalfa et al, 2003; Hou et al, 2006; Muddashetty et al, 2007; Zalfa et al, 2007) requires proteasome-mediated degradation (Ehlers, 2003). These findings suggest an interplay between mRNA localization and FMRP degradation that is integrated with neuronal activity and directly regulated by the ubiquitin-proteasome system
Summary
Reviewed by: Linda Van Aelst, Cold Spring Harbor Laboratory, USA Ingrid Bureau, Institut de Neurobiologie de la Méditerranée, France. Emerging evidence indicates that RNA binding proteins, ribosomes, translation factors and mRNAs encoding proteins critical to synaptic structure and function localize to neuronal processes. Considerable evidence indicates that alterations in synaptic strength are locked-in by alterations in structural remodeling These morphological changes include induction of new dendritic spines, enlargement of spines already extant, and the splitting of single spines into two or more functional synapses (Bourne and Harris, 2008; Holtmaat et al, 2009; Newpher and Ehlers, 2009). GENERAL FEATURES OF mRNA TRANSLATION mRNA translation, a complex process involving the participation of many proteins and RNAs, is generally divided into three phases: initiation, elongation, and termination Each of these steps serves as a point of regulation to control the amount of protein that is produced, initiation is by far the most important and the salient features of this segment are important to keep in mind when considering how synapse stimulation induces changes in the translational apparatus. Phosphorylation of 4E-BP either directly or indirectly by the kinase mammalian Target of Rapamycin (mTOR) causes it to dissociate from eIF4E, thereby liberating the factor to bind both the cap and eIF4G and initiate translation (Gingras et al, 1999)
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