TY - JOUR
T1 - Association with proteasome determines pathogenic threshold of polyglutamine expansion diseases
AU - Kim, Meewhi
AU - Bezprozvanny, Ilya
N1 - Funding Information:
The authors thank to Leah Taylor for administrative assistance, members of Bezprozvanny and Kim laboratories for helpful discussions and to George De Martino for comments on the manuscript. This work was supported by the Russian Science Foundation Grant 19-15-00184 (IB) and by the National Institutes of Health grant R01NS056224 (IB). IB is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - 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 (Qth). A pathogenic threshold is unique for each disease but the reasons for variability in Qth 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 Qth value [1]. To explain the correlation between the polarity of the flanking sequences and Qth we performed quantitative analysis of interactions between polyQ-expanded proteins and proteasome. Based on structural and theoretical modeling, we predict that Qth 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 Qth 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.
AB - 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 (Qth). A pathogenic threshold is unique for each disease but the reasons for variability in Qth 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 Qth value [1]. To explain the correlation between the polarity of the flanking sequences and Qth we performed quantitative analysis of interactions between polyQ-expanded proteins and proteasome. Based on structural and theoretical modeling, we predict that Qth 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 Qth 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.
KW - Ataxin
KW - Huntingtin
KW - Mathematical modeling
KW - Pathogenic conformation
KW - Polyglutamine disorders
KW - Proteasome dysfunction
KW - Protein structure modeling
KW - polyQ
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U2 - 10.1016/j.bbrc.2020.12.065
DO - 10.1016/j.bbrc.2020.12.065
M3 - Article
C2 - 33370719
AN - SCOPUS:85098123230
SN - 0006-291X
VL - 536
SP - 95
EP - 99
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
ER -