Abstract
Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.
Highlights
Huntington’s disease (HD) is a monogenic disorder of the central nervous system that was first described in 1872 by George Huntington (Huntington, 2003)
Aberrant mRNA-protein interactions can occur and modify translation of disease-associated mRNAs. One example of such an aberrant interaction is binding of the MID1 to mutant HTT mRNA (Krauss et al, 2013)
MID1 induces protein translation of its target mRNAs (Krauss et al, 2013; Hettich et al, 2014; Köhler et al, 2014; Griesche et al, 2016), and in HD cell models, the interaction of MID1 and mutant HTT RNA leads to an increased translation rate of neurotoxic polyglutamine protein (Krauss et al, 2013)
Summary
HD is a monogenic disorder of the central nervous system that was first described in 1872 by George Huntington (Huntington, 2003). The CAGrepeat length-dependent binding of the MID1-protein complex leads to an increased translation rate of mutant HTT mRNAs, resulting in a toxic gain of function. This phenomenon of translational induction by MID1 is found in models of other CAG repeat diseases, since the association of the MID1-complex to CAG repeats is independent of the repeatflanking sequences (Griesche et al, 2016). Our data show that MID1 expression is aberrantly increased in HD brains, both in patients as well as in a mouse model This together with the aberrant activity of MID1 on mutant HTT protein synthesis makes MID1 a promising target of an intervention strategy. These data validate that the MID1 complex is a valuable drug target and pave the way for the further development and refinement of small molecule inhibitors of this interaction as potential therapies for HD
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