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

Mehdi Eshraghi, Pabalu P. Karunadharma, Juliana Blin, Neelam Shahani, Emiliano P. Ricci, Audrey Michel, Nicolai T. Urban, Nicole Galli, Manish Sharma, Uri Nimrod Ramírez-Jarquín, Katie Florescu, Jennifer Hernandez and Srinivasa Subramaniam ()
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Mehdi Eshraghi: The Scripps Research Institute, Department of Neuroscience
Pabalu P. Karunadharma: The Scripps Research Institute, Genomic Core
Juliana Blin: Laboratory of Biology and Cellular Modelling at Ecole Normale Supérieure of Lyon, RNA Metabolism in Immunity and Infection Lab, LBMC
Neelam Shahani: The Scripps Research Institute, Department of Neuroscience
Emiliano P. Ricci: Laboratory of Biology and Cellular Modelling at Ecole Normale Supérieure of Lyon, RNA Metabolism in Immunity and Infection Lab, LBMC
Audrey Michel: RiboMaps Ltd
Nicolai T. Urban: The Max Planck Neuroscience Institute
Nicole Galli: The Scripps Research Institute, Department of Neuroscience
Manish Sharma: The Scripps Research Institute, Department of Neuroscience
Uri Nimrod Ramírez-Jarquín: The Scripps Research Institute, Department of Neuroscience
Katie Florescu: The Scripps Research Institute, Department of Neuroscience
Jennifer Hernandez: The Scripps Research Institute, Department of Neuroscience
Srinivasa Subramaniam: The Scripps Research Institute, Department of Neuroscience

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21637-y

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