Proteomics

Dataset Information

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Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease


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 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.

INSTRUMENT(S): LTQ Orbitrap Elite, Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Huntington Disease

SUBMITTER: Ranen Aviner  

LAB HEAD: Judith Frydman

PROVIDER: PXD026012 | Pride | 2024-03-13

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
B20180702-25-PV_Q8_80S.raw Raw
B20180702-27-PV_Q73_80S.raw Raw
B20180702-28-PV_Q8_Pol.raw Raw
B20180702-29-PV_Q8_Pol.raw Raw
B20180702-30-PV_Q8_Pol.raw Raw
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