Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome

Ifrim, Marius F.; Williams, Kathryn R.; Bassell, Gary J.

doi:10.1523/jneurosci.2802-14.2015

Cited by 83 publications

(84 citation statements)

References 61 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Work from several laboratories has demonstrated SMN-dependent defects in the localization and local translation of axonal mRNAs and mRBPs. Since the discovery of defective axonal localization of ␤-actin mRNA and protein in SMA motor neurons (Rossoll et al, 2003), SMN has been found to regulate the axonal localization of transcripts encoding growth-associated protein 43 (GAP43) and neuritin/cpg15 (Akten et al, 2011;Fallini et al, 2011Fallini et al, , 2014Fallini et al, , 2016Hubers et al, 2011;Sanchez et al, 2013) (Fig. 1).…”

Section: Dysregulation Of Mrnp Assembly and Localization In Spinal Mumentioning

confidence: 99%

Dysregulation of mRNA Localization and Translation in Genetic Disease

et al. 2016

View full text Add to dashboard Cite

RNA-binding proteins (RBPs) acting at various steps in the post-transcriptional regulation of gene expression play crucial roles in neuronal development and synaptic plasticity. Genetic mutations affecting several RBPs and associated factors lead to diverse neurological symptoms, as characterized by neurodevelopmental and neuropsychiatric disorders, neuromuscular and neurodegenerative diseases, and can often be multisystemic diseases. We will highlight the physiological roles of a few specific proteins in molecular mechanisms of cytoplasmic mRNA regulation, and how these processes are dysregulated in genetic disease. Recent advances in computational biology and genomewide analysis, integrated with diverse experimental approaches and model systems, have provided new insights into conserved mechanisms and the shared pathobiology of mRNA dysregulation in disease. Progress has been made to understand the pathobiology of disease mechanisms for myotonic dystrophy, spinal muscular atrophy, and fragile X syndrome, with broader implications for other RBP-associated genetic neurological diseases. This gained knowledge of underlying basic mechanisms has paved the way to the development of therapeutic strategies targeting disease mechanisms.

show abstract

Section: Dysregulation Of Mrnp Assembly and Localization In Spinal Mumentioning

confidence: 99%

Dysregulation of mRNA Localization and Translation in Genetic Disease

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The hyperactivation of mGluR5 signaling, as well as the neuronal and behavioral deficits resulting from FMRP deficiency can be corrected by application of a mGluR5 antagonists (Bear et al, 2004; Bear, 2005; Tucker et al, 2006; Dolen et al, 2007; Price et al, 2007; Wilson and Cox, 2007; Auerbach and Bear, 2010; Osterweil et al, 2010; Levenga et al, 2011b; Michalon et al, 2012, 2014; Ronesi et al, 2012; Lohith et al, 2013; Pop et al, 2014). The activation of FMRP subsequently regulates the local synthesis of several other synaptic proteins, including AMPAR, CaMKII, and PSD95, which in turn modulates the activity-dependent dynamics and plasticity of dendritic spines (Muddashetty et al, 2007; Nakamoto et al, 2007; Kao et al, 2010; Ifrim et al, 2015). In addition, the Rac-PAK pathway is upregulated and coincides with the disruptive dendritic phenotype in the absence of FMRP (Lee et al, 2003; Hayashi et al, 2007; Chen et al, 2010a; Bongmba et al, 2011).…”

Section: Specific Syndromic Disorder Related Genesmentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

show abstract

“…Several strategies have been developed to visualize de novo protein synthesis (Aakalu et al, 2001; Butko et al, 2012; Dieterich et al, 2010; Gao et al, 2008; Ifrim et al, 2015; Ju et al, 2004; Kim et al, 2013; Leung et al, 2006; Lin et al, 2008; Lin and Tsien, 2010; Martin et al, 2005; Raab-Graham et al, 2006; Rodriguez et al, 2006; Schmidt et al, 2009; Smith et al, 2005; Tatavarty et al, 2012; Wang et al, 2009; Yu et al, 2006). A recent methodological advance (SunTag) engineers protein epitopes that bind and concentrate constitutively expressed GFP affinity ligands to visualize nascent polypeptides and overcomes limitations of time resolution consequent to requirement for GFP fluorescence maturation (Tanenbaum et al, 2014; Wang et al, 2016; Yan et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Real-Time Imaging Reveals Properties of Glutamate-Induced Arc/Arg 3.1 Translation in Neuronal Dendrites

Park

Lee

et al. 2016

Neuron

View full text Add to dashboard Cite

Summary The immediate early gene Arc (also Arg3.1) produces rapid changes in synaptic properties that are linked to de novo translation. Here we develop a novel translation reporter that exploits the rapid maturation and “flash” kinetics of Gaussia luciferase (Gluc) to visualize Arc translation. Following glutamate stimulation, discrete Arc-Gluc bioluminescent flashes representing sites of de novo translation are detected within 15 s at distributed sites in dendrites, but not spines. Flashes are episodic, lasting ∼20 s, and may be unitary or repeated at ~minute intervals at the same sites. Analysis of flash amplitudes suggests they represent the quantal product of one or more polyribosomes, while inter-flash intervals appear random, suggesting they arise from a stochastic process. Surprisingly, glutamate-induced translation is dependent on Arc open reading frame. Combined observations support a model in which stalled ribosomes are reactivated to rapidly generate Arc protein.

show abstract

Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome

Cited by 83 publications

References 61 publications

Dysregulation of mRNA Localization and Translation in Genetic Disease

Dysregulation of mRNA Localization and Translation in Genetic Disease

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Real-Time Imaging Reveals Properties of Glutamate-Induced Arc/Arg 3.1 Translation in Neuronal Dendrites

Contact Info

Product

Resources

About