Kailash Nabariya, Deepti
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Publication Access status: Open Access , Intracellular and intercellular transport of RNA organelles in CXG repeat disorders: The strength of weak tiesRNA is a vital biomolecule, the function of which is tightly spatiotemporally regulated. RNA organelles are biological structures that either membrane-less or surrounded by membrane. They are produced by the all the cells and indulge in vital cellular mechanisms. They include the intracellular RNA granules and the extracellular exosomes. RNA granules play an essential role in intracellular regulation of RNA localization, stability and translation. Aberrant regulation of RNA is connected to disease development. For example, in microsatellite diseases such as CXG repeat expansion disorders, the mutant CXG repeat RNA’s localization and function are affected. RNA is not only transported intracellularly but can also be transported between cells via exosomes. The loading of the exosomes is regulated by RNA-protein complexes, and recent studies show that cytosolic RNA granules and exosomes share common content. Intracellular RNA granules and exosome loading may therefore be related. Exosomes can also transfer pathogenic molecules of CXG diseases from cell to cell, thereby driving disease progression. Both intracellular RNA granules and extracellular RNA vesicles may serve as a source for diagnostic and treatment strategies. In therapeutic approaches, pharmaceutical agents may be loaded into exosomes which then transport them to the desired cells/tissues. This is a promising target specific treatment strategy with few side effects. With respect to diagnostics, disease-specific content of exosomes, e.g., RNA-signatures, can serve as attractive biomarker of central nervous system diseases detecting early physiological disturbances, even before symptoms of neurodegeneration appear and irreparable damage to the nervous system occurs. In this review, we summarize the known function of cytoplasmic RNA granules and extracellular vesicles, as well as their role and dysfunction in CXG repeat expansion disorders. We also provide a summary of established protocols for the isolation and characterization of both cytoplasmic and extracellular RNA organelles.Source Type:Article386 194 - Some of the metrics are blocked by yourconsent settings
Publication Access status: Open Access , Investigating the Crosstalk between Small Extracellular vesicles and RNA granules in Huntington’s Disease(2025)Huntington’s disease (HD) is a neurodegenerative disorder marked by progressive neuronal degeneration, with no current cure. Recent research suggests that RNA granules (such as stress granules and p-bodies) and small extracellular vesicles (sEVs) play critical roles in cellular dysfunction in HD. Both compartments share features like liquid-liquid phase separation (LLPS) and RNA-binding proteins, but the relationship between mutant huntingtin (mHTT) and their shared content remains unexplored. In this study, we analyze the transcriptomic and proteomic profiles of sEVs and RNA granules in a model expressing mHTT to understand their molecular interactions in HD. Our results show significant changes in gene expression in both sEVs and RNA granules, with a notable decrease in sEVs. Long non-coding RNAs (lncRNAs) were abundant in both compartments, and their expression shifted in HD, suggesting their involvement in disease progression. Additionally, 139 genes in our marker list are regulated by the Repressor Element 1 Silencing Transcription Factor (REST), which is disrupted in HD. Three marker genes (SNHG7, LHR1 LNC1610-1, and lnc-DUXA-1) were validated in RNA granules using RNA-FISH, showing partial co-localization with YB1-positive stress granules. qRT-PCR confirmed increased expression of all five marker genes (lnc-SLC30A5-6, SNHG7, SNHG12, LHR1-LNC1610-1, and lnc-DUXA-1) in HD RNA granules, with three markers showing increased expression in sEVs, though two exhibited high variability. To validate the relevance of our findings, we compared the expression patterns of HD sEV marker genes with a recently published RNA sequencing dataset of plasma EVs from HD patients. Our results show a stronger correlation between the pre-HD group in the patient dataset and our cell model, suggesting that our model better reflects the early stages of HD progression. We also identified distinct protein profiles in HD sEVs and RNA granules, with 13 shared proteins, highlighting a unique molecular signature for HD. STRING and KEGG pathway analyses revealed enriched pathways related to neurodegenerative diseases, suggesting broader impacts on neurodegenerative processes. Overlapping GO terms between RNA granules and sEVs point to functional interactions, particularly in RNA transport and metabolism. Notably, WDR1, a protein associated with mHTT-RNA complexes, was identified in both HD sEVs and RNA granules, suggesting its role in HD pathogenesis by influencing RNA granule formation and facilitating intercellular communication via sEVs. Our findings demonstrate that mHTT alters the composition of sEVs and RNA granules in HD. The detection of miRNAs, zinc finger proteins (ZNFs), and lncRNAs in sEVs suggests that HD cells may attempt to manage stress and intercellular signaling. The identification of overlapping proteins like WDR1, RANBP6, and ITGAV offers potential biomarkers and therapeutic targets. This study enhances our understanding of HD pathology by revealing the differential sorting of RNA and proteins in HD, with implications for early diagnosis and targeted therapies.Source Type:Doctoral Thesis63 43
