Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington's disease.
Nat Cell Biol
; 26(6): 892-902, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38741019
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Ribossomos
/
Fatores de Iniciação de Peptídeos
/
Proteínas de Ligação a RNA
/
Doença de Huntington
/
Proteína Huntingtina
/
Proteostase
/
Fator de Iniciação de Tradução Eucariótico 5A
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos