Location of polyglutamine track affects pathogenic threshold of polyglutamine expansion diseases - Importance of association with the proteasome

The expansion of glutamine residue track (polyQ) within soluble proteins (Q proteins) is responsible for nine autosomal-dominant genetic neurodegenerative disorders. These disorders develop when polyQ expansion exceeds a specific pathogenic threshold (Q_th) which is unique for each disease. However, the pathogenic mechanisms associated with the variability of Q_th within the family of Q proteins are poorly understood. In the previous publication we proposed that polarity of the regions flanking polyQ track in each protein plays a key role in defining Q_th value (Kim, M. Mol Neurodegener 9 (2014) 45) and that these effects can be explained as a result of interactions between polyQ-expanded protein and proteasome (Kim, M Bezprozvanny, I (2021). Biochem Biophys Res Commun 536:95-99). In the present manuscript we extended our analysis and analyzed effects of location of polyQ-expanded track within the protein sequence. To accomplish this, we divided a family of polyQ-expanded proteins into 3 classes - G1, G2 and G3 groups, which differ by position of polyQ-expanded track in the protein sequence. We determined that polarity of flanking regions have different effect on Q_th. value for each of these classes, and explained these differences by mechanistic analysis of proteasomal function. Our results further support the hypothesis that differences in Q_th. values of pathogenic threshold can be explained by different mode of interactions between polyQ-flanking regions and proteasome and these findings provide novel insight into pathogenic mechanisms of polyQ-expanded disorders.