The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease

Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472, USA.
Brain research (Impact Factor: 2.84). 01/2012; 1462:61-80. DOI: 10.1016/j.brainres.2012.01.016
Source: PubMed


Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable 'prion domain' enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease and Huntington's disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system. This article is part of a Special Issue entitled RNA-Binding Proteins.

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Available from: James Shorter, Oct 11, 2015
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    • "TDP-43 and FUS share many structural similarities (Figure 3) and both are involved in various aspects of mRNA metabolism including splicing, nucleocytoplasmic shuttling, transcription, mRNA stability, and SG dynamics (Lagier-Tourenne et al., 2010). Specifically, they both have prion-like domains (Cushman et al., 2010; King et al., 2012; Li et al., 2013), and the combination of a prionlike domain and a RRM has recently been used to predict genetic modifiers or causes of several neurodegenerative diseases (King et al., 2012). Thus, it has been proposed that these two proteins may participate in a common pathogenic mechanism. "
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    ABSTRACT: Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.
    Frontiers in Cellular Neuroscience 11/2015; 9:423. DOI:10.3389/fncel.2015.00423 · 4.29 Impact Factor
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    • " . , 2013 ) . In animals , PrDs tend to be involved in the regulation of central biological processes and organism development , which in vertebrates includes the development of the neural crest . Hence , many human PrD are found in RNA - binding proteins , which deregulation has previously been associated with several neurodegenerative diseases ( King et al . , 2012 ) . Eukaryote PrD - containing proteins show less functional diversity than bacteria . In fact , here we have collected all the enriched eukaryote functions ( i . e . , transcription , RNA binding , and DNA binding ) in just one cluster ( nucleotide binding ) . Despite this difference , it appears that , independently of the considered "
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    ABSTRACT: Prion proteins were initially associated with diseases such as Creutzfeldt Jakob and transmissible spongiform encephalopathies. However, deeper research revealed them as versatile tools, exploited by the cells to execute fascinating functions, acting as epigenetic elements or building membrane free compartments in eukaryotes. One of the most intriguing properties of prion proteins is their ability to propagate a conformational assembly, even across species. In this context, it has been observed that bacterial amyloids can trigger the formation of protein aggregates by interacting with host proteins. As our life is closely linked to bacteria, either through a parasitic or symbiotic relationship, prion-like proteins produced by bacterial cells might play a role in this association. Bioinformatics is helping us to understand the factors that determine conformational conversion and infectivity in prion-like proteins. We have used PrionScan to detect prion domains in 839 different bacteria proteomes, detecting 2200 putative prions in these organisms. We studied this set of proteins in order to try to understand their functional role and structural properties. Our results suggest that these bacterial polypeptides are associated to peripheral rearrangement, macromolecular assembly, cell adaptability, and invasion. Overall, these data could reveal new threats and therapeutic targets associated to infectious diseases.
    Frontiers in Microbiology 10/2015; 6. DOI:10.3389/fmicb.2015.01123 · 3.99 Impact Factor
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    • "Curiously, many of the proteins known to segregate into RNP granules contain repetitive putatively disordered domains (Kato et al., 2012). A subset of these proteins, including 29 found in humans, contains a disordered domain rich in polar and aromatic residues and nearly devoid of aliphatic and charged amino acids, resembling the aggregation-prone glutamine/asparagine-rich domains of yeast prion proteins such as Sup35 (King et al., 2012). Hence these domains are also referred to as ''prion-like domains.'' "
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    ABSTRACT: Phase-separated states of proteins underlie ribonucleoprotein (RNP) granules and nuclear RNA-binding protein assemblies that may nucleate protein inclusions associated with neurodegenerative diseases. We report that the N-terminal low-complexity domain of the RNA-binding protein Fused in Sarcoma (FUS LC) is structurally disordered and forms a liquid-like phase-separated state resembling RNP granules. This state directly binds the C-terminal domain of RNA polymerase II. Phase-separated FUS lacks static structures as probed by fluorescence microscopy, indicating they are distinct from both protein inclusions and hydrogels. We use solution nuclear magnetic resonance spectroscopy to directly probe the dynamic architecture within FUS liquid phase-separated assemblies. Importantly, we find that FUS LC retains disordered secondary structure even in the liquid phase-separated state. Therefore, we propose that disordered protein granules, even those made of aggregation-prone prion-like domains, are dynamic and disordered molecular assemblies with transiently formed protein-protein contacts.
    Molecular cell 10/2015; 60(2). DOI:10.1016/j.molcel.2015.09.006 · 14.02 Impact Factor
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