title: Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington's disease.
abstract: Huntington's disease (HD) is a neurodegenerative disease caused by an abnormal expansion in the polyglutamine (polyQ) track of the Huntingtin (HTT) protein. The severity of the disease depends on the polyQ repeat length, arising only in patients with proteins having 36 repeats or more. Previous studies have shown that the aggregation of N-terminal fragments (encoded by HTT exon 1) underlies the disease pathology in mouse models and that the HTT exon 1 gene product can self-assemble into amyloid structures. Here, we provide detailed structural mechanisms for aggregation of several protein fragments encoded by HTT exon 1 by using the associative memory, water-mediated, structure and energy model (AWSEM) to construct their free energy landscapes. We find that the addition of the N-terminal 17-residue sequence ([Formula: see text]) facilitates polyQ aggregation by encouraging the formation of prefibrillar oligomers, whereas adding the C-terminal polyproline sequence ([Formula: see text]) inhibits aggregation. The combination of both terminal additions in HTT exon 1 fragment leads to a complex aggregation mechanism with a basic core that resembles that found for the aggregation of pure polyQ repeats using AWSEM. At the extrapolated physiological concentration, although the grand canonical free energy profiles are uphill for HTT exon 1 fragments having 20 or 30 glutamines, the aggregation landscape for fragments with 40 repeats has become downhill. This computational prediction agrees with the critical length found for the onset of HD and suggests potential therapies based on blocking early binding events involving the terminal additions to the polyQ repeats.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.|Department of Bioengineering, Rice University, Houston, TX 77005.
authors.forename: Mingchen
authors.initials: M
authors.lastname: Chen
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; pwolynes@rice.edu.|Department of Chemistry, Rice University, Houston, TX 77005.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wolynes
mesh_terms: D003198:Computer Simulation; D003599:Cytoskeleton; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002479:Inclusion Bodies; D008956:Models, Chemical; D010455:Peptides; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D010455:Peptides; D066329:Protein Aggregates; C011083:polyproline; C097188:polyglutamine
keywords: Huntington’s disease; aggregation; aggregation free energy landscape; critical length; solubility