title: The evolutionary scope and neurological disease linkage of yeast-prion-like proteins in humans.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Reviewed by Istvan Simon and Alexander Schleiffer. For the full reviews, please go to the Reviewers' comments section.
authors.affiliation: Department of Biology, McGill University, Montreal, QC, Canada.
authors.forename: Lu
authors.initials: L
authors.lastname: An
authors.affiliation: Department of Biology, McGill University, Montreal, QC, Canada. paul.harrison@mcgill.ca.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harrison
mesh_terms: D005075:Biological Evolution; D019143:Evolution, Molecular; D008040:Genetic Linkage; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics*; D000072002:Prion Proteins / Q000009:adverse effects*; D040901:Proteomics; D012441:Saccharomyces cerevisiae
chemical_list: D000072002:Prion Proteins
keywords: Amyloid; Asparagine; Disease; Evolution; Glutamine; Human; Neurodegenerative; Poly-Q expansion; Prion; Yeast