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Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Author

Listed:
  • Sybille Krauß

    (German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 25, 53127)

  • Nadine Griesche

    (German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 25, 53127)

  • Ewa Jastrzebska

    (Charité University Hospital
    Max Planck Institute for Molecular Genetics)

  • Changwei Chen

    (Medical Research Institute, Ninewels Hospital & Medical School)

  • Désiree Rutschow

    (Medical Research Institute, Ninewels Hospital & Medical School)

  • Clemens Achmüller

    (Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI)
    Innsbruck Medical University
    Present address: Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria)

  • Stephanie Dorn

    (German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 25, 53127)

  • Sylvia M. Boesch

    (Innsbruck Medical University)

  • Maciej Lalowski

    (Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
    Biomedicum Helsinki, Meilahti Clinical Proteomics Core Facility and Folkhälsan Research Center, University of Helsinki, PO Box 63, (Haartmaninkatu 8), Helsinki FI-00014, Finland)

  • Erich Wanker

    (Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch)

  • Rainer Schneider

    (Max Planck Institute for Molecular Genetics
    Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI))

  • Susann Schweiger

    (Max Planck Institute for Molecular Genetics
    Medical Research Institute, Ninewels Hospital & Medical School
    Institute for Human Genetics, Medical School, University of Mainz)

Abstract

Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington’s disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1–protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A- and mammalian target of rapamycin-dependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-complex may serve as a therapeutic target for the treatment of CAG repeat expansion disorders.

Suggested Citation

  • Sybille Krauß & Nadine Griesche & Ewa Jastrzebska & Changwei Chen & Désiree Rutschow & Clemens Achmüller & Stephanie Dorn & Sylvia M. Boesch & Maciej Lalowski & Erich Wanker & Rainer Schneider & Susan, 2013. "Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex," Nature Communications, Nature, vol. 4(1), pages 1-9, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2514
    DOI: 10.1038/ncomms2514
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