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.