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Background  Prions are proteinaceous particles that propagate alternative protein conformations/states to further copies of the same proteins, and are transmitted from cell-to-cell, and organism-to-organism. Prions are usually made of the beta-sheet rich assemblies termed amyloid. The original prion protein PrP causes devastating neurodegenerative disorders in humans and other mammals. In the yeast  Saccharomyces cerevisiae , many prion-forming proteins have been observed; a prominent feature of these proteins is an intrinsically disordered domain rich in glutamine (Q) and asparagine (N) residues. Several human proteins that are yeast-prion-like, in particular those with poly-glutamine (poly-Q) expansions, have been experimentally implicated in human neurodegenerative diseases.    Results  Here, we have constructed a comprehensive list of human yeast-prion-like proteins that are linked to human neurological disease. Surprisingly, different methods to annotate yeast-prion-like proteins in humans have limited intersection. However, independent of annotation method, we find that human yeast-prion-like proteins as a group have a statistically significant genetic linkage to neurological disease, that is caused specifically by linkage to neurodegenerative diseases. This is despite: (i) no especially high expression of yeast-prion-like proteins in the central nervous system, or (ii) no general enrichment of intrinsically disordered proteins in neurological/neurodegenerative diseases. Cytoskeletal proteins are significantly overrepresented in the set of human yeast-prion-like neurological proteins. Whether involved in neurological pathomechanisms or not, yeast-prion-like proteins in humans have very limited conservation outside of  Deuterostomia  (< ~10 %) with only a handful having prion-like character in both human and  S. cerevisiae . The only such protein with a disease linkage is PUB1/TIA1, which functions as a stress granule component. Thus, the yeast-prion-like character of proteins linked to neurodegenerative diseases has not been conserved over the deep evolutionary time since the last common ancestor of yeasts and humans.    Conclusion  Our results provide a comprehensive picture of yeast-prion-like proteins in humans and contribute to the strategic basis for experimental investigation of the link between yeast-prion-like protein character and neurological disease.    Reviewers  Reviewed by Istvan Simon and Alexander Schleiffer. For the full reviews, please go to the Reviewers’ comments section.    Electronic supplementary material  The online version of this article (doi:10.1186/s13062-016-0134-5) contains supplementary material, which is available to authorized users.

The evolutionary scope and neurological disease linkage of yeast-prion-like proteins in humans