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BRAIN RESEARCH 1462 (2012) 61–80

Available online at www.sciencedirect.com



The tip of the iceberg: RNA-binding proteins with prion-like
domains in neurodegenerative disease
Oliver D. Kinga,⁎, Aaron D. Gitlerb,⁎⁎, James Shorterc,⁎⁎⁎

Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472, USA
Department of Genetics,Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA 94305-5120, USA
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar-Chance Laboratories,
422 Curie Boulevard, Philadelphia, PA 19104, USA



Article history:

Prions are self-templating protein conformers that are naturallytransmitted between individ-

Accepted 7 January 2012

uals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial,

Available online 21 January 2012

neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine res-


iduesunifies the majority of yeast prion proteins. Deletion of this domain precludes


prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An al-

RNA-binding protein

gorithm designed to detect prion domains has successfully identified 19 domains that can confer


prion behavior. Scouring the human genome with this algorithm enriches aselect group of RNA-


binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion do-


main. 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

Amyotrophic lateral sclerosis

prion candidates are inexorablyemerging, 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 Huntington's disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing
prion candidates, form cytoplasmicinclusions 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 candidatesidentified 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 ispart 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: king@bbri.org (O.D. King), agitler@stanford.edu (A.D. Gitler), jshorter@mail.med.upenn.edu (J. Shorter).
0006-8993/$ – see front matter © 2012 Elsevier B.V. All rights reserved.doi:10.1016/j.brainres.2012.01.016


BRAIN RESEARCH 1462 (2012) 61–80

Prions: unusual protein-based genetic elements . . . . . . . . . . . . . . . . . .
Increased awareness of prion-related phenomena in neurodegenerative disease
Yeast prions: good or evil or both? . . . . . . . . . . . . . . . . . . . . . . . . . .
Distinctive, portable prion domains encode...
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