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BRAIN RESEARCH 1462 (2012) 61–80

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,⁎⁎⁎
a

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
c
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar-Chance Laboratories,
422 Curie Boulevard, Philadelphia, PA 19104, USA
b

ARTICLE INFO

ABSTRACT

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-

Keywords:

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

Prion

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

TDP-43

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

FUS

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

TAF15

main. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of

EWSR1

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-

Neurodegeneration

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

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BRAIN RESEARCH 1462 (2012) 61–80

Contents
1.
Prions: unusual protein-based genetic elements . . . . . . . . . . . . . . . . . .
2.
Increased awareness of prion-related phenomena in neurodegenerative disease
3.
Yeast prions: good or evil or both? . . . . . . . . . . . . . . . . . . . . . . . . . .
4.
Distinctive, portable prion domains encode...
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