Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington's disease.

Aviner, Ranen; Lee, Ting-Ting; Masto, Vincent B; Li, Kathy H; Andino, Raul; Frydman, Judith

Aviner, Ranen; Lee, Ting-Ting; Masto, Vincent B; Li, Kathy H; Andino, Raul; Frydman, Judith.

Afiliación

Aviner R; Department of Biology and Department of Genetics, Stanford University, Stanford, CA, USA.
Lee TT; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Masto VB; Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA.
Li KH; Department of Biology and Department of Genetics, Stanford University, Stanford, CA, USA.
Andino R; Department of Biology and Department of Genetics, Stanford University, Stanford, CA, USA.
Frydman J; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.

Nat Cell Biol ; 26(6): 892-902, 2024 Jun.

Article en En | MEDLINE | ID: mdl-38741019

ABSTRACT

ABSTRACT

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

Asunto(s)

Factor 5A Eucariótico de Iniciación de Traducción; Proteína Huntingtina; Enfermedad de Huntington; Factores de Iniciación de Péptidos; Péptidos; Proteostasis; Proteínas de Unión al ARN; Ribosomas; Enfermedad de Huntington/metabolismo; Enfermedad de Huntington/genética; Enfermedad de Huntington/patología; Animales; Péptidos/metabolismo; Péptidos/genética; Proteína Huntingtina/genética; Proteína Huntingtina/metabolismo; Humanos; Ribosomas/metabolismo; Ribosomas/genética; Factores de Iniciación de Péptidos/metabolismo; Factores de Iniciación de Péptidos/genética; Proteínas de Unión al ARN/metabolismo; Proteínas de Unión al ARN/genética; Ratones; Ratones Transgénicos; Modelos Animales de Enfermedad; Estrés Fisiológico; Encéfalo/metabolismo; Encéfalo/patología; Expansión de Repetición de Trinucleótido/genética

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Ribosomas / Factores de Iniciación de Péptidos / Proteínas de Unión al ARN / Enfermedad de Huntington / Proteína Huntingtina / Proteostasis / Factor 5A Eucariótico de Iniciación de Traducción Límite: Animals / Humans Idioma: En Revista: Nat Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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