Aberrant expression of the MID1 protein in neurons of Huntington's disease brain

Huntington's disease (HD) is caused by a CAG repeat expansion mutation in the Huntingtin (HTT) gene that transcribes into mRNA and translates into a polyglutamine tract. The mutant HTT gene products drive pathological changes that result in neurodegeneration. The mutant CAG repeat RNA contributes to cellular dysfunction by aberrantly recruiting RNA-binding proteins. For example, the mutant HTT transcript associates with a protein complex containing the MID1 protein. This aberrant recruitment of the MID1 protein complex results in an increased translation of mutant HTT. MID1 expression is abnormally high in both the brains of HD mouse models and HD patients. However, the cell type in which MID1 is overexpressed in HD brains remains obscure. Here, we investigated the MID1 expression in different brain cell types of an HD mouse model. Therefore, we separated neurons, astrocytes and microglia via magnetic sorting and show that MID1 is overexpressed in neurons of an HD mouse model. Moreover, we stained MID1 in brain sections of HD mice via immunohistochemistry and observed MID1 overexpressing cells in cortex. This finding shows that MID1 is highly expressed in neurons-the most vulnerable cell type in HD-underlining its important role in the neurodegenerative process. This supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a promising therapeutic approach.