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

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.

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Interestingly, the MID1 complex appears to bind to expanded CAG repeats with higher affinity than to non-expanded repeats. In agreement with a role for MID1 and mTORC1 in promoting canonical translation of these transcripts, translation is increased upon inhibition of PP2Ac, and decreased upon knockdown of MID1 or inhibition of mTORC1 (Griesche et al, 2016; Krauss et al, 2013). Whether this mechanism also contributes to RAN translation is unknown.…”

Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

“…We have recently shown that mRNAs carrying CAG repeats bind to a protein complex containing the ubiquitin ligase midline 1 (MID1) in a repeat size-dependent manner. Through ubiquitination MID1 regulates PP2A (protein phosphatase 2A) and mTOR (mechanistic target of rapamycin) activities and the translation of associated mRNAs ( Krauss et al, 2013 ; Griesche et al, 2016 ). Disruption of the MID1/PP2A/mTOR protein complex leads to an increase of PP2A activity, a decrease of mTOR activity and a reduction of translation rates of mRNAs with expanded CAG repeats ( Krauss et al, 2013 ).…”

New developments in RAN translation: insights from multiple diseases

“…There are also additional regulatory connections between the polyglutamine disorders that affect protein translation. For example, the MID1-translation regulatory protein complex binds and regulates the translation of CAG expansions in the canonical ATG-initiated frame in a length dependent manner in HD and several SCAs [26]. It will be interesting to determine if this regulatory mechanism also influences RAN translation.…”