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Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease.

ABSTRACT: Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease.

PROVIDER: PRJNA611600 | ENA |

REPOSITORIES: ENA

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Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [Ribo-seq]

Project description:The polyglutamine expansion of huntingtin (mHtt) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis. Depletion of mHtt enhances protein synthesis and increases the speed of ribosome translocation, while mHtt directly inhibits protein synthesis in vitro. We found interactions of ribosomal proteins and translating ribosomes with mHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicated a widespread shift in ribosome occupancy toward the 5’ and 3’ end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. Thus, mHtt impedes ribosomal translocation during translation by promoting ribosome stalling, a novel mechanistic defect that can be exploited for HD therapeutics.

2020-07-22 | GSE146674 | GEO

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [RNA-seq]

2020-07-22 | GSE146673 | GEO

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease (mRNA-Seq)

2021-02-13 | GSE166695 | GEO

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [Ribo-seq]

Project description:Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [Ribo-seq]

| PRJNA611609 | ENA

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [RNA-seq]

Project description:Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [RNA-seq]

| PRJNA611610 | ENA

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease (mRNA-Seq)

Project description:Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease (mRNA-Seq)

| PRJNA701625 | ENA

Mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

Project description:Ribosomes translocate one codon at a time in mRNA during protein synthesis, but the regulators of ribosome translocation and their impact on neurodegenerative disease remain poorly understood. Here, we show that huntingtin (Htt) and its poly-Q expanded form, mHtt, a cause of Huntington disease (HD), promotes ribosome stalling and suppresses protein synthesis in vivo and in vitro. We found that fragile mental retardation protein (FMRP), a known promoter of ribosome stalling, is upregulated in HD cells and patients’ tissue. Unexpectedly, FMRP depletion fails to reverse mHtt-mediated ribosome stalling in HD cells. mHtt binds directly to ribosomes in a RNase-sensitive manner and interacts with ribosomal proteins. Combining high-resolution ribosome footprint profiling (Ribo-Seq) and RNA-Seq, we provide a global snapshot of stalling on mRNA transcripts, with a shift in ribosome occupancy toward the 5’ and 3’ end and single-codon unique pauses in HD cells. We also found ribosomes that appear to have stalled in mHtt mRNA before CAG repeat expansion. Thus, Htt regulates protein synthesis via ribosome stalling mechanisms and in turn may affect mRNA elongation, which may be exploited for HD therapeutics.

2021-04-06 | PXD017115 | Pride

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease.

Project description: Not available

| S-EPMC7935949 | biostudies-literature

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease.

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-22 | GSE146675 | GEO

Huntington disease protein accelerates tumour development and metastasis

Project description:Huntington disease is a severe neurological disorder caused by an abnormal polyglutamine expansion in the N-terminal of the huntingtin protein. Here we show that breast tumours appear earlier when mutant huntingtin is expressed in an activated polyomavirus middle T antigen (PyVT) mouse breast cancer model as compared to the control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern revealing increases in the IGF-1/Akt signalling, epithelial-mesenchymal transition and metastatic properties. Indeed, polyQ-huntingtin expressing tumours show hyper-activation of Akt pathway. Also, when mutant huntingtin is expressed, cancer cells in culture change morphology and the levels of cell adhesion and mesenchymal markers are affected in primary tumour or corresponding derived cells. As a consequence, PyVT induced lung metastasis is higher in Huntington disease mice than in the control mice. Finally, analysis of cases of Huntington disease patients developing breast cancer may suggest an increased aggressiveness of breast cancer when compared to the control population.

2014-04-14 | GSE28685 | GEO

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