Association with proteasome determines pathogenic threshold of polyglutamine expansion diseases

Expansion of glutamine residue track (polyQ) within soluble protein is responsible for eight autosomal-dominant genetic neurodegenerative disorders. These disorders affect cerebellum, striatum, basal ganglia and other brain regions. Each disease develops when polyQ expansion exceeds a pathogenic threshold (Q_th). A pathogenic threshold is unique for each disease but the reasons for variability in Q_th within this family of 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 [1]. To explain the correlation between the polarity of the flanking sequences and Q_th we performed quantitative analysis of interactions between polyQ-expanded proteins and proteasome. Based on structural and theoretical modeling, we predict that Q_th value is determined by the energy of polar interaction of the flanking regions with the polyQ and proteasome. More polar flanking regions facilitate unfolding of α-helical polyQ conformation adopted inside the proteasome and as a result, increase Qth. Predictions of our model are consistent with Q_th values observed in clinic for each of the eight polyQ-expansion disorders. Our results suggest that the agents that can destabilize polyQ α-helical structure may have a beneficial therapeutic effect for treatment of polyQ-expansion disorders.