BRES-42024; No. of pages: 20; 4C: 7, 8, 10, 12, 13 BRAIN RESEARCH XX (2012) XXX– XXX Available online at www.sciencedirect.com www.elsevier.com/locate/brainres Review The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease Oliver D. Kinga,⁎, Aaron D. Gitlerb,⁎⁎, James Shorterc,⁎⁎⁎ aBoston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472, USA bDepartment of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA 94305-5120, USA cDepartment of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA ARTICLE INFO ABSTRACT Article history: Prions are self-templating protein conformers that are naturally transmitted between individ- Accepted 7 January 2012 uals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A dis- Keywords: tinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine res- Prion idues unifies the majority of yeast prion proteins. Deletion of this domain precludes RNA-binding protein prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An al- TDP-43 gorithm designed to detect prion domains has successfully identified 19 domains that can confer FUS prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA- TAF15 binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion do- EWSR1 main. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of Amyotrophic lateral sclerosis these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding Neurodegeneration prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastat- ing neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease and Hun- tington'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 pa- tients 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 con- nected 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. © 2012 Elsevier B.V. All rights reserved. ⁎ Corresponding author. ⁎⁎ Corresponding author. ⁎⁎⁎ Corresponding author. Fax: +1 215 898 4217. E-mail addresses: [email protected] (O.D. King), [email protected] (A.D. Gitler), [email protected] (J. Shorter). 0006-8993/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2012.01.016 Please cite this article as: King, O.D., et al., The tip of the iceberg: RNA-binding proteins with prion-like domains in neurode- generative disease, Brain Res. (2012), doi:10.1016/j.brainres.2012.01.016 2 BRAIN RESEARCH XX (2012) XXX– XXX Contents 1. Prions: unusual protein-based genetic elements ....................................... 0 2. Increased awareness of prion-related phenomena in neurodegenerative disease ..................... 0 3. Yeast prions: good or evil or both? ............................................... 0 4. Distinctive, portable prion domains encode yeast prion behavior . ........................... 0 5. Algorithms designed to detect yeast prion domains ..................................... 0 6. An abundance of human RNA-binding proteins with prion-like domains .......................... 0 7. TDP-43: the first of many? ................................................... 0 8. FUS, another RRM-bearing prion candidate implicated in neurodegeneration ....................... 0 9. TAF15 emerges in ALS and FTLD-U. .............................................. 0 10. EWSR1 emerges in FTLD-U ................................................... 0 11. Prion-like domains in sarcoma and leukemia ......................................... 0 12. Functional role of prion-like domains?............................................. 0 13. Genetic landscape of ALS and other RNA-binding proteinopathies . ........................... 0 14. The tip of the iceberg ...................................................... 0 Acknowledgments ........................................................... 0 References ............................................................... 0 1. Prions: unusual protein-based genetic intrinsic ability to self-replicate conformation in the prevail- elements ing environmental conditions (Duennwald and Shorter, 2010; Ghaemmaghami et al., 2009; Li et al., 2010a; 2011; Roberts et Even under physiological conditions, it is now clear that cer- al., 2009; Shorter, 2010; Wang et al., 2008a; Weissmann et al., tain primary sequences enable proteins to adopt a range of al- 2011). In this sense, prion disorders can be viewed as a conflict ternative structures that are each capable of conformational between levels of selection. The initiation of selfish prion rep- self-replication via templating the conversion of other copies lication launches a microevolutionary process in which the of the same protein (Alberti et al., 2009; Gendoo and Harrison, prion replicator initially prospers and amplifies but ultimately 2011; Goldschmidt et al., 2010; Halfmann et al., 2011; Sawaya destroys the host. The mammalian nervous system is particu- et al., 2007; Toombs et al., 2010; Wiltzius et al., 2009). Typically, larly vulnerable to this conflict and can become severely and this conversion to a self-templating form radically alters pro- selectively devastated by prionogenesis (Shorter, 2010; tein function. Thus, a dramatic change in phenotype idiosyn- Weissmann et al., 2011). cratic to the function of the specific protein in question can rapidly ensue as self-templating forms deplete other con- formers from the population. Sometimes these self- 2. Increased awareness of prion-related templating protein conformers can be naturally transmitted phenomena in neurodegenerative disease between individuals and promote phenotypic change. In these cases, the self-templating structures are termed prions In recent years, awareness has increased that a similar microevo- (Colby and Prusiner, 2011; Cushman et al., 2010; Halfmann lutionary process might be at work in other neurodegenerative and Lindquist, 2010; Shorter, 2010; Weissmann et al., 2011). diseases connected with protein misfolding, including Alzhei- Prions are perhaps most infamous as the etiological agents mer's disease, Parkinson's disease and Huntington's disease of infectious neurodegenerative diseases in mammals, includ- (Shorter, 2010). Indeed, it now appears probable that these devas- ing bovine spongiform encephalopathy, which can even tra- tating disorders are also underpinned by the spread of self- verse species barriers via the food chain and cause variant templating protein conformers. Here, self-templating forms Creutzfeldt–Jakob disease in humans (Colby and Prusiner, spread from cell to cell within contiguous regions of the 2011; Collinge and Clarke, 2007; Weissmann et al., 2011). In- brains of afflicted individuals, thereby spreading the specific neu- deed, it is now possible to induce prion disease in wild-type rodegenerative phenotypes distinctive to the protein being con- mice by simply inoculating recombinant prion protein (PrP) verted to the self-templating form (Brundin et al., 2010; that has been previously folded into a self-templating form Cushman et al., 2010; Dunning et al., 2011; Goedert et al., 2010; in the presence of poly-anions and lipid in vitro (Wang et al., Polymenidou and Cleveland, 2011; Prusiner, 1984; Walker et al., 2010, 2011a, 2011b). This simple transforming principle helps 2006). In these instances, transmission is usually restricted to establish the unfamiliar view of self-templating protein struc- withinatissueorwithinanindividual. Transmission between in- tures as genetic material (Fink, 2005). dividuals does not seem to occur naturally, but can be induced in As self-replicating entities, prions are protein-based genet- experimental model systems (Clavaguera et al., 2009; Desplats et ic elements, which are inescapably bound by the laws of nat- al., 2009; Eisele et al., 2010; Meyer-Luehmann et al., 2006). This ural selection. Thus, the concentration of specific self- type of phenomena has been termed prion-like and Adriano templating forms will ebb and flow depending upon their Aguzzi has even coined the term ‘prionoid’ to distinguish these Please cite this article as: King, O.D., et al., The tip of the iceberg: RNA-binding proteins with prion-like domains in neurode- generative disease, Brain Res. (2012), doi:10.1016/j.brainres.2012.01.016 BRAIN RESEARCH XX (2012)