title: Polyglutamine Aggregation in Huntington Disease: Does Structure Determine Toxicity?
abstract: Huntington disease is a dominantly inherited disease of the central nervous system. The mutational expansion of polyglutamine beyond a critical length produces a toxic gain of function in huntingtin and results in neuronal death. In the course of the disease, expanded huntingtin is proteolyzed, becomes abnormally folded, and accumulates in oligomers, fibrils, and microscopic inclusions. The aggregated forms of the expanded protein are structurally diverse. Structural heterogeneity may explain why polyglutamine-containing aggregates could paradoxically be either toxic or neuroprotective. When defined, the toxic structures could then specifically be targeted by prophylactic or therapeutic drugs aimed at inhibiting polyglutamine aggregation.
authors.affiliation: Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France.
authors.forename: Guylaine
authors.initials: G
authors.lastname: Hoffner
authors.affiliation: Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. philippe.djian@parisdescartes.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Djian
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001718:Birefringence; D001921:Brain / Q000648:ultrastructure; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D002479:Inclusion Bodies; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D058105:Polymerization; D066329:Protein Aggregates / Q000502:physiology; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021381:Protein Transport; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D000939:Epitopes; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine; D010447:Peptide Hydrolases
keywords: Amyloid; Fibrils; Huntingtin; Inclusions; Oligomers; β-Sheets