Neurodegeneration and RNA‐binding proteins

Advanced Review

Laura De Conti, Marco Baralle, Emanuele Buratti

Published Online: Sep 22 2016

DOI: 10.1002/wrna.1394

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In the eukaryotic nucleus, RNA‐binding proteins (RBPs) play a very important role in the life cycle of both coding and noncoding RNAs. As soon as they are transcribed, in fact, all RNA molecules within a cell are bound by distinct sets of RBPs that have the task of regulating its correct processing, transport, stability, and function/translation up to its final degradation. These tasks are particularly important in cells that have a complex RNA metabolism, such as neurons. Not surprisingly, therefore, recent findings have shown that the misregulation of genes involved in RNA metabolism or the autophagy/proteasome pathway plays an important role in the onset and progression of several neurodegenerative diseases. In this article, we aim to review the recent advances that link neurodegenerative processes and RBP proteins. WIREs RNA 2017, 8:e1394. doi: 10.1002/wrna.1394 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease

Schematic representation of the prion‐like seeding of aggregation. RNA‐binding proteins characterized by a prion‐like domain have often been found to be aggregation prone and can be part of stress granules upon stress induction. Under pathological conditions, such as aggregation‐enhancing mutations or chronic stress, the RNA‐binding proteins in the stress granules can assume a stable structure that can trigger further uptake of RNA‐binding proteins and mRNAs. This can give rise to inclusions that resemble the pathological hallmark of several neurological diseases. Furthermore, molecules carrying these long‐lived aberrant conformations may eventually spread from cell‐to‐cell in a seed‐like behavior. This can therefore mediate the spread of the aggregates during the course of the disease.

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Schematic representation of RNA compartmentalization in the cytoplasm. Once RNAs exit the nucleus they can immediately undergo translation or can be ‘transiently silenced’ (in order to be translated at the right moment in the right place). To do so, highly dynamic and interacting RNA granules are formed where the RNAs can be transported or stored until their translation in active polysomes needs to take place.

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RNA‐binding proteins and their implication in different aspects of neuronal metabolism. RNA‐binding proteins listed according to their cellular role. The ones highlighted in red are RNA‐binding proteins predominantly or exclusively expressed in neurons. Mutations or expression dysregulation of many of these proteins have been associated with the occurrence of neurological disorders.

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