Krauß, Sybille
Preferred name
Krauß, Sybille
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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:Article1 13 - Some of the metrics are blocked by yourconsent settings
Publication Access status: Open Access , Transcriptomic analysis of intracellular RNA granules and small extracellular vesicles: Unmasking their overlap in a cell model of Huntington's diseaseHuntington's disease (HD) arises from the abnormal expansion of a CAG repeat in the HTT gene. The mutant CAG repeat triggers aberrant RNA-protein interactions and translates into toxic aggregate-prone polyglutamine protein. These aberrant RNA-protein ineractions also seed the formation of cytoplasmic liquid-like granules, such as stress granules. Emerging evidence demonstrates that granules formed via liquid-liquid phase separation can mature into gel-like inclusions that persist within the cell and may act as precursor to aggregates that occur in patients' tissue. Thus, deregulation of RNA granules is an important component of neurodegeneration. Interestingly, both the formation of intracellular membrane-less organelles like stress granules and the secretion of small extracellular vesicles (sEVs) increase upon stress and under disease conditions. sEVs are lipid membrane-bound particles that are secreted from all cell types and may participate in the spreading of misfolded proteins and aberrant RNA-protein complexes across the central nervous system in neurodegenerative diseases like HD. In this study, we performed a comparative transcriptomic analysis of sEVs and RNA granules in an HD model. RNA granules and sEVs were isolated from an inducible HD cell model. Both sEVs and RNA granules were isolated from induced (HD) and non-induced (control) cells and analyzed by RNA sequencing. Our comparative analysis between the transcriptomics data of HD RNA granules and sEVs showed that: (I) intracellular RNA granules and extracellular RNA vesicles share content, (II) several non-coding RNAs translocate to RNA granules, and (III) the composition of RNA granules and sEVs is affected in HD cells. Our data showing common transcripts in intracellular RNA granules and extracellular sEVs suggest that formation of RNA granules and sEV loading may be related. Moreover, we found a high abundance of lncRNAs in both control and HD samples, with several transcripts under REST regulation, highlighting their potential role in HD pathogenesis and selective incorporation into sEVs. The transcriptome cargo of RNA granules or sEVs may serve as a source for diagnostic strategies. For example, disease-specific RNA-signatures of sEVs can serve as biomarker of central nervous system diseases. Therefore, we compared our dataset to transcriptomic data from HD patient sEVs in blood. However, our data suggest that the cell-type specific signature of sEV-secreted RNAs as well as their high variability may make it difficult to detect these biomarkers in blood.Source Type:Article7 9
