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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Flore, 2021. "Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21637-y
    DOI: 10.1038/s41467-021-21637-y
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    Cited by:

    1. Chisa Shiraishi & Akinobu Matsumoto & Kazuya Ichihara & Taishi Yamamoto & Takeshi Yokoyama & Taisuke Mizoo & Atsushi Hatano & Masaki Matsumoto & Yoshikazu Tanaka & Eriko Matsuura-Suzuki & Shintaro Iwa, 2023. "RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Elena Plessa & Lien P. Chu & Sammy H. S. Chan & Oliver L. Thomas & Anaïs M. E. Cassaignau & Christopher A. Waudby & John Christodoulou & Lisa D. Cabrita, 2021. "Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Ekaterina Borisova & Andrew G. Newman & Marta Couce Iglesias & Rike Dannenberg & Theres Schaub & Bo Qin & Alexandra Rusanova & Marisa Brockmann & Janina Koch & Marieatou Daniels & Paul Turko & Olaf Ja, 2024. "Protein translation rate determines neocortical neuron fate," Nature Communications, Nature, vol. 15(1), pages 1-25, December.

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