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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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HeLa Cells
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Humans
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Huntingtin Protein
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Luciferases / metabolism
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Mice
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Microtubule Proteins / metabolism*
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / metabolism*
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Nucleotide Motifs
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Protein Binding
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Protein Biosynthesis / genetics*
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Protein Phosphatase 2 / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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TOR Serine-Threonine Kinases / metabolism
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Transcription Factors / metabolism*
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Trinucleotide Repeat Expansion / genetics*
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Ubiquitin-Protein Ligases
Substances
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HTT protein, human
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Huntingtin Protein
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Microtubule Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Messenger
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Transcription Factors
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Luciferases
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MID1 protein, human
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Ubiquitin-Protein Ligases
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MTOR protein, human
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TOR Serine-Threonine Kinases
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Protein Phosphatase 2