Neuronal cells rely on macro- and micro-cellular compartmentalization to rapidly process information, and respond locally to external stimuli. Such a cellular organization is achieved via the assembly of neuronal ribonucleoprotein (RNP) granules, dynamic membrane-less organelles enriched in RNAs and associated regulatory proteins. In this review, we discuss how these high-order structures transport mRNAs to dendrites and axons, and how they contribute to the spatio-temporal regulation of localized mRNA translation. We also highlight how recent biophysical studies have shed light on the mechanisms underlying neuronal RNP granule dynamic assembly, remodeling and maturation, in both physiological and pathological contexts.
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- The lab has been studying RNA-binding proteins (RBPs) and their complexes (RNPs) since the 1980s, focusing on their roles in regulating gene expression after transcription.* -
- Research uncovered links between RBPs, specific diseases like fragile X syndrome and spinal muscular atrophy, highlighting the connection between RNA biology and health conditions.* -
- The findings show that the diverse range of RNAs and RBPs can lead to increased complexity and potential disorders, suggesting a promising area for future research and discoveries in RNA science.*
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Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC, United States.
Introduction: Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN.
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Dev Cell
January 2025
Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:
Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo.
View Article and Find Full Text PDFPhase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.
Int J Mol Sci
August 2024
Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada.
The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases.
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bioRxiv
August 2024
Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Neurobiology Research, Roanoke, Virginia.
Localization of mRNAs to dendrites is a fundamental mechanism by which neurons achieve spatiotemporal control of gene expression. Translationally repressed neuronal mRNA transport granules, also referred to as ribonucleoprotein particles (RNPs), have been shown to be trafficked as single or low copy number RNPs and as larger complexes with multiple copies and/or species of mRNAs. However, there is little evidence of either population in intact neuronal circuits.
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