HD is a monogenic disorder of the central nervous system that was first described in 1872 by George Huntington (Huntington, 2003). HD is caused by an expansion mutation of a CAG repeat within the HTT gene. This CAG repeat translates into a polyglutamine tract in the HTT protein. Since the mutation was discovered in the 1990s (MACDONALD, 1993), research mainly focused on the mutant polyglutamine protein, which forms aggregates in the patient’s brain and is considered a pathological hallmark. However, in the last couple of years several studies showed that it is not solely the polyglutamine protein that drives pathogenic processes, but the mutant RNA transcript is also involved in cellular dysfunction [reviewed in (Nalavade et al., 2013; Schilling et al., 2016; Heinz et al., 2021)]. The main concept of a toxic gain-of-function of the expanded CAG repeat RNA is that the mutant CAG repeat represents an aberrant binding site for RNA-binding proteins, that get sequestered to and carry out an abnormal function in conjunction with the CAG repeat RNA. For example, the mutant HTT transcript aberrantly recruits the Midline1 (MID1) protein. MID1 first aroused attention in 1997, when mutations in MID1 were discovered as the cause of Opitz-BBB/G syndrome (OS), which is characterized by malformations of the ventral midline. These include hypospadias, hypertelorism, heart defects, cleft lip and palate and structural brain abnormalities. In addition, intellectual disability and/or developmental delay occur in approximately 30 percent of affected individuals. Since the discovery that MID1 is involved in the pathogenesis of OS, several functional studies on this protein were performed. MID1 belongs to the protein family of RING finger proteins and contains several conserved domains: a RING finger, two B-Boxes, a coiled-coil domain, a Fibronectin type-III domain, and a B30.2/SPRY domain. While all these domains generally are involved in diverse protein-protein or nucleic acid-protein interactions, some of the domains of MID1 have specific known functions: for example, via its RING finger domain, MID1 executes an E3 ubiquitin ligase activity, MID1 forms homo-dimers via its coiled-coil domain, and MID1 associates to microtubules via its C-terminal domains. To date several studies have been conducted that indicate that MID1 is a central player in the cell and is involved in several cellular processes, both in healthy tissue as well as in diseases [reviewed in (Winter et al., 2016)]. However, after the discovery that MID1 is responsible for OS, it took another decade until the first connection between MID1 and neurodegenerative diseases was found (Kickstein et al., 2010). With respect to neurodegenerative diseases, one important aspect of MID1 function is its ability to bind to mRNA and induce translation. This translation inducer function of MID1 can be explained by the recruitment of the translation machinery to the respective MID1 target mRNA. In this respect, MID1 has been shown to assemble a protein complex that contains various subunits of both the eukaryotic translation initiation factor complex (eIF complex) and the ribosome (Matthes et al., 2018a). This translational regulator function is of particular interest in neurodegenerative diseases and had first been linked to Alzheimer’s disease (AD). AD is the most common form of dementia in the elderly and is characterized by two neuropathological hallmarks: intracellular neurofibrillary tangles, that are mainly composed of an aberrantly high phosphorylated and thus aggregate-prone protein called Tau, and extracellular amyloid plaques, which are mainly formed by the Aβ peptide, which results from aberrant cleavage of the amyloid precursor protein (APP). Strikingly, MID1 interacts with mRNAs and proteins involved in formation of both of these pathological hallmarks. On one hand, by regulating the ubiquitin-dependent degradation of PP2A, the major Tau phosphatase, MID1 can influence Tau phosphorylation (Kickstein et al., 2010; Schweiger et al., 2017). On the other hand, by binding to and regulating the translation of two mRNAs that are involved in formation of Aβ (the APP mRNA and the BACE1 mRNA), MID1 also influences the extracellular amyloid plaques (Hettich et al., 2014; Matthes et al., 2018a). Analysis of the expression level of MID1 in AD brain tissue suggest that MID1 is aberrantly high expressed in patients and thus an abnormally high MID1 activity may push pathogenesis in the course of neurodegeneration (Schweiger et al., 2017). In 2013, a first connection between MID1 and polyglutamine disorders like HD had been shown (Krauss et al., 2013). Here, the mutant HTT transcript aberrantly recruits the MID1 protein complex and this binding increases with CAG repeat length. MID1 in turn recruits the translation machinery to the expanded CAG repeat mRNA, and thus, association of the MID1 complex drives an aberrantly high translation of mutant HTT mRNA, resulting in overproduction of mutant polyglutamine protein.

Protein expression from specific mRNA molecules is tightly regulated in a cell-type-dependent manner. In disease conditions, 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). Functionally, 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). Thus, MID1 may be a disease modifier in HD. However, the expression level as well as the expression pattern of MID1 in HD brain tissue has not been studied thus far and previous studies mainly described MID1 expression in embryos or very young individuals. In mice MID1 is expressed in different tissues depending on the age. In embryos between E8.5–14.5 as well as in newborn animals it is expressed in the central nervous system [reviewed in (Winter et al., 2016)]. In humans MID1 is also expressed in different tissues depending on age, in 5–7 weeks old embryos in the central nervous system [reviewed in (Winter et al., 2016)]. In line, our data show that MID1 is detectable in central nervous system. However, the tissues we tested here were from mature individuals (adult). Strikingly, our data show a significantly upregulated expression of MID1 under disease-conditions, supporting our hypothesis that MID1 by pushing towards polyglutamine protein synthesis is a disease-modifier in HD and targeting of MID1 may represent one therapeutic approach to halt HD disease progression. In line, different studies in which either the binding of MID1 to mutant HTT mRNA (Matthes et al., 2018b) or the assembly of the MID1 protein complex had been pharmacologically blocked (Arnoux et al., 2018), showed reduced HTT translation and reduced behavioral aberrations in HD models. Recent studies show that lowering HTT levels in HD (in antisense oligonucleotide (AON) therapies) is a promising therapeutic approach (Kordasiewicz et al., 2012; Østergaard et al., 2013; Sciences, 2021). However, HTT is an essential protein and thus, it is possible that permanent reduction in HTT expression may cause long-term side-effects. In line, recent clinical trials targeting both, normal and mutant alleles, give first evidence that lowering HTT below a critical level may not be tolerated well (Deeprose and Rosser, 2021; Heinz et al., 2021). On benefit of targeting MID1 to reduce HTT protein expression over targeting the HTT transcript itself is that MID1 mostly acts on the disease allele, while keeping expression of the normal allele untouched. Furthermore, MID1 is aberrantly upregulated in HD and should be normally expressed at a low level, thus, reducing MID1 in HD may just bring the expression back to normal and therefore may cause less side-effects. Moreover, loss of function of MID1 (like in Opitz syndrome) leads developmental problems, but causes no adult-life effects. Thus, targeting MID1 in adults has most likely no detrimental effect.