title: Pathogenic and non-pathogenic polyglutamine tracts have similar structural properties: towards a length-dependent toxicity gradient.
abstract: Abnormally expanded polyglutamine (polyQ) tracts provide a gain of toxic functions to nine otherwise unrelated human proteins and induce progressive neurodegenerative diseases. Over the past ten years, it was suggested that only polyQ tracts longer than a specific threshold adopt a particular structure, which would be the cause of the apparent polyQ length-dependent toxicity threshold observed in polyQ diseases. We have used a combination of biochemical and biophysical approaches to compare the structural properties of polyQ of pathogenic and non-pathogenic lengths under various conditions. We observe that pathogenic and non-pathogenic polyQ, as soluble species and upon interaction with a partner, during aggregation, or as mature aggregates, display very similar structural properties. PolyQ length only influences the aggregation kinetics and, to a lesser extent, the stability of the aggregates. We thus propose that polyQ toxicity does not depend on a structural transition occurring above a specific threshold, but rather that polyQ tracts are inherently toxic sequences, whose deleterious effect gradually increases with their length. We discuss how polyQ properties and other cellular factors may explain the existence of an apparent polyQ length-dependent toxicity threshold.
authors.affiliation: Department of Molecular Pathology, Institut de Génétique et Biologie Moléculaire et Cellulaire, UMR 7104-CNRS/INSERM/ULP, BP10142, 67404 Illkirch Cédex, CU de Strasbourg, France.
authors.forename: Fabrice A C
authors.initials: FA
authors.lastname: Klein
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.forename: Laura
authors.initials: L
authors.lastname: Masino
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Zeder-Lutz
authors.forename: Hélène
authors.initials: H
authors.lastname: Nierengarten
authors.forename: Mustapha
authors.initials: M
authors.lastname: Oulad-Abdelghani
authors.forename: Danièle
authors.initials: D
authors.lastname: Altschuh
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Yvon
authors.initials: Y
authors.lastname: Trottier
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000633:toxicity
chemical_list: D010455:Peptides; D011506:Proteins; C097188:polyglutamine