Regulation of mRNA Translation by MID1: A Common Mechanism of Expanded CAG Repeat RNAs.

Nadine Griesche,Stephanie Weber,Marlena Rohm,Frank Matthes,Verena Pesch,Georg Auburger,Sybille Krauss,Judith Schilling

doi:10.3389/fncel.2016.00226

Nadine Griesche, Stephanie Weber + Show 6 more

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https://doi.org/10.3389/fncel.2016.00226

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Abstract

Expansion of CAG repeats, which code for the disease-causing polyglutamine protein, is a common feature in polyglutamine diseases. RNA-mediated mechanisms that contribute to neuropathology in polyglutamine diseases are important. RNA-toxicity describes a phenomenon by which the mutant CAG repeat RNA recruits RNA-binding proteins, thereby leading to aberrant function. For example the MID1 protein binds to mutant huntingtin (HTT) RNA, which is linked to Huntington's disease (HD), at its CAG repeat region and induces protein synthesis of mutant protein. But is this mechanism specific to HD or is it a common mechanism in CAG repeat expansion disorders? To answer this question, we have analyzed the interaction between MID1 and three other CAG repeat mRNAs, Ataxin2 (ATXN2), Ataxin3 (ATXN3), and Ataxin7 (ATXN7), that all differ in the sequence flanking the CAG repeat. We show that ATXN2, ATXN3, and ATXN7 bind to MID1 in a CAG repeat length-dependent manner. Furthermore, we show that functionally, in line with what we have previously observed for HTT, the binding of MID1 to ATXN2, ATXN3, and ATXN7 mRNA induces protein synthesis in a repeat length-dependent manner. Our data suggest that regulation of protein translation by the MID1 complex is a common mechanism for CAG repeat containing mRNAs.

Highlights

CAG repeat expansion diseases are the most common forms of inherited neurodegenerative diseases
To test if the flanking regions influence the binding of MID1 to CAG repeat mRNAs, we tested the binding of MID1 to ATXN2, ATXN3, and ATXN7 mRNAs
We asked if this binding and translational regulation by MID1 is specific for HTT or if this is a common mechanism involved in several CAG repeat diseases

Summary

Introduction

CAG repeat expansion diseases are the most common forms of inherited neurodegenerative diseases. They are caused by expansion mutations of the trinucleotide CAG in the respective disease-causing genes. These genes are functionally unrelated and the only common motif of these genes is the CAG repeat. If the CAG repeat is located within the protein-coding region it encodes a polyglutamine stretch. Intraneuronal aggregation of the polyglutamine proteins is a pathological hallmark of several CAG repeat diseases and the production of polyglutamine proteins is linked to neurotoxicity (Rudnicki and Margolis, 2003; Shao and Diamond, 2007; Fiszer and Krzyzosiak, 2014). In addition to neurotoxic effects of polyglutamine protein, there is emerging evidence showing that RNA-mediated mechanisms contribute to neurotoxicity in polyglutamine diseases (reviewed in Nalavade et al, 2013 and Schilling et al, 2016)

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