Abstract
The life cycle of an mRNA is a complex process that is tightly regulated by interactions between the mRNA and RNA-binding proteins, forming molecular machines known as RNA granules. Various types of these membrane-less organelles form inside cells, including neurons, and contribute critically to various physiological processes. RNA granules are constantly in flux, change dynamically and adapt to their local environment, depending on their intracellular localization. The discovery that RNA condensates can form by liquid–liquid phase separation expanded our understanding of how compartments may be generated in the cell. Since then, a plethora of new functions have been proposed for distinct condensates in cells that await their validation in vivo. The finding that dysregulation of RNA granules (for example, stress granules) is likely to affect neurodevelopmental and neurodegenerative diseases further boosted interest in this topic. RNA granules have various physiological functions in neurons and in the brain that we would like to focus on. We outline examples of state-of-the-art experiments including timelapse microscopy in neurons to unravel the precise functions of various types of RNA granule. Finally, we distinguish physiologically occurring RNA condensation from aberrant aggregation, induced by artificial RNA overexpression, and present visual examples to discriminate both forms in neurons.
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Acknowledgements
This long-term project is supported by the DFG (KI 502/9-1, P no. 506658941). The authors thank T. Abel, G. Bassell, L. Becker, F. Besse, S. Das, S. Fernandez-Moya, A. Gladfelter, A. Hubstenberger, J. Lippincott-Schwartz, J. Ninkovic, G. Pilz and N. Sonenberg for valuable comments and B. Nitz for figure design.
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Glossary
- Cajal bodies
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Biomolecular condensates in eukaryotic nuclei. Prominent markers include coilin and survival motor neuron protein, among mRNA splicing factors. Important for assembling spliceosomal small nuclear ribonucleoproteins.
- Cis-acting signals
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Cis-acting signals or cis-acting sequences — often located in the 3′-UTR — that direct mRNAs to their destination in dendrites near synapses. Often, they are referred to as localization elements or zipcodes. These sequences or secondary structures are recognized by trans-acting factors or RNA-binding proteins.
- Liquid–liquid phase separation
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(LLPS). Also known as liquid–liquid demixing, LLPS is a biophysical framework describing the formation of biomolecular condensates, in which a homogeneous liquid mixture separates into different liquid phases, each containing different components.
- Low complexity
-
Proteins found in biomolecular condensate often harbour intrinsically disordered, low-complexity sequence domains that mediate phase separations. These regions lack a dominant 3D structure, with the consequence that the protein can adopt a range of conformational changes. Prominent examples are the RNA helicase DDX4, a constituent germ granule component, LAF-1, FMRP, FUS and TDP-43.
- Nucleolus
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The most prominent nuclear body representing a biomolecular condensate in a eukaryotic nucleus. Prominent markers include nucleolin and fibrillarin. Its primary function is to produce and assemble ribosomes.
- RNA condensates
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Formed by multivalent macromolecular interactions between ribonucleoprotein particles. They are thought to have profound impacts on the compartmentalization of cytoplasm within neurons.
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Kiebler, M.A., Bauer, K.E. RNA granules in flux: dynamics to balance physiology and pathology. Nat. Rev. Neurosci. 25, 711–725 (2024). https://doi.org/10.1038/s41583-024-00859-1
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DOI: https://doi.org/10.1038/s41583-024-00859-1
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