[Dataset] The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity

Huntington's disease is a neurodegenerative disorder caused by a CAG expansion in the first exon of the HTT gene, resulting in an extended polyglutamine (poly-Q) tract in huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood due...

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Detalles Bibliográficos
Autores: Elena-Real, Carlos A., Sagar, Amin, Urbanek, Annika, Popovic, Matija, Morató, Anna, Estaña, Alejandro, Fournet, Aurélie, Doucet, Christine, Lund, Xamuel L., Shi, Zhen-Dan, Costa, Luca, Thureau, Aurélien, Allemand, Frédéric, Swenson, Rolf E., Milhiet, Pierre-Emmanuel, Crehuet, Ramon, Barducci, Alessandro, Cortés, Juan, Sinnaeve, Davy, Sibille, Nathalie, Bernadó, Pau
Tipo de recurso: conjunto de datos
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/384345
Acceso en línea:http://hdl.handle.net/10261/384345
https://digital.csic.es/handle/10261/303567
Access Level:acceso abierto
Palabra clave:Huntington’s disease
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Descripción
Sumario:Huntington's disease is a neurodegenerative disorder caused by a CAG expansion in the first exon of the HTT gene, resulting in an extended polyglutamine (poly-Q) tract in huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood due to its intrinsic flexibility and the strong compositional bias. The systematic application of site-specific isotopic labeling has enabled residue-specific NMR investigations of the poly-Q tract of pathogenic httex1 variants with 46 and 66 consecutive glutamines. Integrative data analysis reveals that the poly-Q tract adopts long α-helical conformations propagated and stabilized by glutamine side chain to backbone hydrogen bonds. We show that α-helical stability is a stronger signature in defining aggregation kinetics and the structure of the resulting fibrils than the number of glutamines. Our observations provide a structural perspective of the pathogenicity of expanded httex1 and pave the way to a deeper understanding of poly-Q-related diseases.

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