Abstract
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 in mouse HD striatal neuronal cells. Depletion of mHtt enhances protein synthesis and increases the speed of ribosomal translocation, while mHtt directly inhibits protein synthesis in vitro. Fmrp, a known regulator of ribosome stalling, is upregulated in HD, but its depletion has no discernible effect on protein synthesis or ribosome stalling in HD cells. We found interactions of ribosomal proteins and translating ribosomes with mHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicates 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 elongation, a mechanistic defect that can be exploited for HD therapeutics.
Highlights
The polyglutamine expansion of huntingtin causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear
We identified a high polysome/ monosome (PS/MS) ratio in the HD-homo compared to the HDhet or control cells (Fig. 1A, B) by integrating the area under the curve from raw profiles (Supplementary Fig. S1)
We hypothesized that the high PS/MS ratio in HD-homo cells reflected a more actively translating mRNA in the HD-homo cells
Summary
The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Ribosomes move one codon at a time along mRNA during protein synthesis, a fundamental process in all living cells During this translocation (aka ribosome movement), the ribosomes pause for a variety of reasons, such as codon usage, peptide properties, mRNA structure, and tRNA availability, or solely due to a continuously changing cellular demand[1,2,3,4,5,6,7]. Conditional deletion of Htt in the mouse brain results in a defect in corticostriatal development, as well as induces hyperactivity, acute pancreatitis, and age-dependent neurodegenerative-like phenotype[26,27,28]. MHTT does not appear to perturb development in mouse models, it has been shown to interfere with cortical neurogenesis in the human fetal brain[32,33]
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