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Review
. 2022 Dec 16:9:1000932.
doi: 10.3389/fmolb.2022.1000932. eCollection 2022.

Intracellular and intercellular transport of RNA organelles in CXG repeat disorders: The strength of weak ties

Deepti Kailash Nabariya  1 , Annika Heinz  1 , Sabrina Derksen  1 , Sybille Krauß  1
Affiliations
Review

Intracellular and intercellular transport of RNA organelles in CXG repeat disorders: The strength of weak ties

Deepti Kailash Nabariya et al. Front Mol Biosci. .

Abstract

RNA 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.

Keywords: CXG repeat disorders; RNA granules; RNA toxicity; exosomes; neurodegeneration; neuronal RNA granules; processing bodies (p-bodies; PB); stress granule (SG).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic overview of different types of intracellular RNA granules in neuronal cell. Promyelocytic leukemia bodies belong to the nuclear granules. Nuclear granules (nucleus dark purple) include nuclear stress bodies (beige, sites of reprogramming of gene expression), Cajal bodies (orange, sites of RNA-processing), Gems (blue, Cajal body assistance), splicing speckles (green, sites of splicing factor modification and storage), paraspeckles (purple, sites of RNA-retention) and the nucleolus (dark grey, site of ribosomal synthesis). Cytoplasmic granules include stress granules (red, sites of translational block), neuronal RNA transport granules (brown, sites of neuronal RNA-transport), and processing bodies (light green, sites of RNA-storage and -decay). Created with BioRender.com.
FIGURE 2
FIGURE 2
Schematic representation of translational induction and translational block via SG-formation. The kinase mTOR (gray) controls the phospho-dependent activity of S6K (purple) and 4E-BP1 (yellow). 4E-BP1 is a negative regulator of translation that represses translation when attached to the 5′ end of an mRNA. Its phosphorylation by mTOR leads to its detachment from the RNA and the release of this translational block. Simultaneously, S6K is phospho-activated by mTOR. Activated S6K phosphorylates its target S6 (purple), a ribosomal subunit. These two mTOR-dependent phosphorylation events promote assembly of the ribosome at the RNA and thus translation. Hydrolysis of GTP to GDP at the protein elF2 (light blue) releases the binding of elF2 to the 40S subunit of the ribosome, allowing the ribosome to assemble and subsequently polysome formation. Upon cell stress (indicated by an orange flash), elF2 is phosphorylated, thus cannot detach from the 40S unit, thereby blocking translation and inducing polysome disassembly. Furthermore, 4E-BP1 is dephosphorylated and thus sticks to the 5′end of the mRNA also inhibiting translation. In addition, proteins such as FMRP (brown), ATXN2L (green) and G3BP1 (dark blue) organize the stalled RNA into SGs. Created with BioRender.com.
FIGURE 3
FIGURE 3
Schematic showing the internal structure and LLPS of RNA granules. RNA granules have a core (dark grey) made of condensed RNA-RNA and RNA-protein complexes, and a shell (light grey) containing RNA-RNA and RNA-protein complexes characterized by weak interactions. Both the shell and the core of the RNA granules build a dynamic system. Both surface exchange (black arrow) and core-shell transitions are possible (red arrow). These are modulated by numerous RNA-protein interactions and require ATP hydrolysis (yellow) as various ATPase complexes (purple) are involved that regulate various steps of granule assembly and stability. Created with BioRender.com.
FIGURE 4
FIGURE 4
Altered RNA granule formation in CXG repeat diseases. (A) In normal cells, several proteins locate to and regulate RNA-processing in PBs (light green), including HTT, AGO2, ATXNL2. During a stress event, phosphorylation of elF2 (light blue) inhibits translation and the translationally silent RNA is organized into SGs (light red) via the activity of several RNA-binding proteins, e.g., FMRP, ATXNL2, or G3BP1. FMRP (brown) is involved in regulation of translation at the pre- and postsynapse. While FMRP blocks translation during transport, it needs to be released from the RNA to allow local synaptic translation. (B) Upon loss of function of FMRP (brown) in FXS, SG formation is inhibited. Similarly, loss of function of ATXNL2 (green) in SCA2 leads to disturbed SG formation. In HD, G3BP1 is overexpressed, leading to increased SG formation and PBs are inhibited. Under disease-conditions with a mutation or lack of HTT or ATXNL2, PB formation is reduced. While RNA-binding proteins like FMRP and HTT normally promote neuronal RNA transport granules, their loss of function decreases RNA transport. Upon loss of function of FMRP, the number of presynaptic Fragile X granules increases together with an increased local translation rate. Created with BioRender.com.
FIGURE 5
FIGURE 5
Schematic representation of extracellular vesicle biogenesis under physiological conditions (A, green) and CXG repeat disease cells (B, red/yellow). (A) Microvesicles are released to the extracellular space by budding from the plasma membrane. Apoptotic bodies arise from membrane protrusions (blebbing) during fragmentation of an apoptotic cell (ES, 2007; Akers et al., 2013; Povea-Cabello et al., 2017; Tricarico et al., 2017). Exosomes are formed by a multistep process that starts with endocytosis (the inward budding of the cell membrane and internalization of cargo into early endosomes). The early endosomes mature into multivesicular bodies (MVBs). By invagination of the MVB membrane intraluminal vesicles (ILVs) are formed. During this process, cytosolic components like proteins, RNAs and lipids are incorporated into ILVs. The ILVs are then released as exosomes from the MVBs into the extracellular space by fusion with the plasma membrane. The exosomes can then be taken up by neighboring cells via endocytosis. (B) In the context of CXG repeat diseases, pathogenic mutant RNA (hairpin, red), micro RNA, mis-spliced RNA and aggregating proteins (red dots) are passed on to neighboring cells via the exosomes. Created with BioRender.com.
FIGURE 6
FIGURE 6
Schematic representation of the consequences of exosomal uptake. Post internalization, the disease-specific exosomal cargo overloads the endosome leading to untapped cargo release into the cytosol. This cargo could disrupt different cellular processes. It promotes aggregation and damages the mitochondrial system thereby increasing exosome release. Autophagic processes are impaired in CXG repeat disorders which facilitates further aggregation. These aggregations further push autophagic system collapse (Cortes and La Spada, 2014).
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