title: Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation.
abstract: The aggregation of polyglutamine (polyQ)-containing proteins is at the origin of nine neurodegenerative diseases. Molecular chaperones prevent the aggregation of polyQ-containing proteins. The exact mechanism by which they interact with polyQ-containing, aggregation-prone proteins and interfere with their assembly is unknown. Here we dissect the mechanism of interaction between a huntingtin exon 1 fragment of increasing polyQ lengths (HttEx1Qn), the aggregation of which is tightly associated with Huntington's disease, and molecular chaperone Hsc70. We show that Hsc70, together with its Hsp40 co-chaperones, inhibits HttEx1Qn aggregation and modifies the structural, seeding, and infectious properties of the resulting fibrils in a polyQ-independent manner. We demonstrate that Hsc70 binds the 17-residue-long N-terminal flank of HttEx1Qn, and we map Hsc70-HttEx1Qn surface interfaces at the residue level. Finally, we show that this interaction competes with homotypic interactions between the N termini of different HttEx1Qn molecules that trigger the aggregation process. Our results lay the foundations of future therapeutic strategies targeting huntingtin aggregation in Huntington disease.
authors.affiliation: From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France monsellier@lebs.cnrs-gif.fr.
authors.forename: Elodie
authors.initials: E
authors.lastname: Monsellier
authors.affiliation: From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Redeker
authors.affiliation: From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Gemma
authors.initials: G
authors.lastname: Ruiz-Arlandis
authors.affiliation: From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Bousset
authors.affiliation: From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France melki@lebs.cnrs-gif.fr.
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
mesh_terms: D005091:Exons / Q000235:genetics*; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D013058:Mass Spectrometry; D018832:Molecular Chaperones / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D011485:Protein Binding
chemical_list: D050883:HSC70 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine
keywords: Heat Shock Protein (HSP); Huntington Disease; Mass Spectrometry (MS); Molecular Chaperone; Neurodegenerative Disease; Polyglutamine; Protein Aggregation