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 alpha-helical polyQ conformation adopted inside the proteasome and as a result, increase Q(th). 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 alpha-helical structure may have a beneficial therapeutic effect for treatment of polyQ-expansion disorders. (C) 2020 Elsevier Inc. All rights reserved.