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

• DOI: 10.1038/ncomms2514
• Publication Date: 2013-02-26T10:19:52Z
• Authors: Sybille Krauß; Nadine Griesche; Ewa Jastrzebska; Changwei Chen; Désiree Rutschow; Clemens Achmüller; Stephanie Dorn; Sylvia M. Boesch; Maciej Lalowski; Erich Wanker; Rainer Schneider; Susann Schweiger
• Keywords: 570; MTOR protein, human; Ubiquitin-Protein Ligases; Blotting, Western; metabolism [Microtubule Proteins]; 610; Nerve Tissue Proteins; metabolism [TOR Serine-Threonine Kinases]; HTT protein, human; metabolism [RNA, Messenger]; genetics [RNA, Messenger]; Mice; 03 medical and health sciences; Animals; Humans; metabolism [Transcription Factors]; Protein Phosphatase 2; RNA, Messenger; Nucleotide Motifs; Luciferases; genetics [Nerve Tissue Proteins]; genetics [Protein Biosynthesis]; Huntingtin Protein; 0303 health sciences; metabolism [Nerve Tissue Proteins]; TOR Serine-Threonine Kinases; Nuclear Proteins; metabolism [Protein Phosphatase 2]; 3. Good health; metabolism [Luciferases]; Protein Biosynthesis; Microtubule Proteins; ddc:500; Trinucleotide Repeat Expansion; metabolism [Nuclear Proteins]; genetics [Trinucleotide Repeat Expansion]; Mid1 protein, human; HeLa Cells; Protein Binding; Transcription Factors

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.