title: Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1.
abstract: Expansions of preexisting polyglutamine (polyQ) tracts in at least nine different proteins cause devastating neurodegenerative diseases. There are many unique features to these pathologies, but there must also be unifying mechanisms underlying polyQ toxicity. Using a polyQ-expanded fragment of huntingtin exon-1 (Htt103Q), the causal protein in Huntington disease, we and others have created tractable models for investigating polyQ toxicity in yeast cells. These models recapitulate key pathological features of human diseases and provide access to an unrivalled genetic toolbox. To identify toxicity modifiers, we performed an unbiased overexpression screen of virtually every protein encoded by the yeast genome. Surprisingly, there was no overlap between our modifiers and those from a conceptually identical screen reported recently, a discrepancy we attribute to an artifact of their overexpression plasmid. The suppressors of Htt103Q toxicity recovered in our screen were strongly enriched for glutamine- and asparagine-rich prion-like proteins. Separated from the rest of the protein, the prion-like sequences of these proteins were themselves potent suppressors of polyQ-expanded huntingtin exon-1 toxicity, in both yeast and human cells. Replacing the glutamines in these sequences with asparagines abolished suppression and converted them to enhancers of toxicity. Replacing asparagines with glutamines created stronger suppressors. The suppressors (but not the enhancers) coaggregated with Htt103Q, forming large foci at the insoluble protein deposit in which proteins were highly immobile. Cells possessing foci had fewer (if any) small diffusible oligomers of Htt103Q. Until such foci were lost, cells were protected from death. We discuss the therapeutic implications of these findings.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Can
authors.initials: C
authors.lastname: Kayatekin
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Kent E S
authors.initials: KE
authors.lastname: Matlack
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: William R
authors.initials: WR
authors.lastname: Hesse
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;Renal Division, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Sohini
authors.initials: S
authors.lastname: Chakrabortee
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Russ
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; and.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;Renal Division, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;Department of Biology andHoward Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139 lindquist_admin@wi.mit.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D005091:Exons; D058851:GPI-Linked Proteins / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011328:Prions / Q000502:physiology*
chemical_list: D058851:GPI-Linked Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C501125:PRND protein, human; D011328:Prions
keywords: prions; protein misfolding
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