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Title: HSP70 as a target for correction of Wilson disease causing ATP7B mutants
Author: Concilli, Mafalda
ISNI:       0000 0004 6421 3224
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2017
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Copper (Cu) is an essential micronutrient, which operates as a cofactor of enzymes regulating a wide range of critical physiological processes. However, Cu overload compromises the redox balance in cells and tissues causing serious toxicity. Removal of excess Cu from the body is driven be Cu-transporting ATPase ATP7B, which sequesters the potentially toxic metal and mediates its excretion into the bile. Mutations in the ATP7B result in Wilson disease (WD) that is caused by the toxic accumulation of Cu in the liver due to the loss of ATP7B function. The most frequent ATP7B mutant, H1069Q, still preserves a significant Cu-transporting activity, but undergoes retention and degradation in the endoplasmic reticulum (ER). Thus, rescue of ATP7B-H1069Q from the ER is expected to recover mutant function and, hence, would be beneficial for a large group of WD patients. Unfortunately, specific targets as well as safe drugs for correction of ATP7B-H1069Q mutant remain to be uncovered. Comparing interactomes of WT and H1069Q variants of ATP7B, I found HSP70 as a specific mutant interactor that regulates ER retention and degradation of ATP7B-H1069Q. HSP70 suppression (with either RNAi or allosteric inhibitor) improved stability of the mutant and facilitated its export from the ER to the Golgi and post-Golgi copper excretion sites. These findings prompted me to look for a safe way to inhibit HSP70 and rescue the ATP7B mutant. To this end several bioinformatics tools were employed to search for FDA-approved drugs that modulate HSP70 expression or exhibit structural similarity to HSP70 inhibitors. As a result, Domperidone and glucocorticoid receptor agonists were identified and validated as effective correctors of ATP7B mutant. In summary, my findings suggest a key role for HSP70 in proteostasis of ATP7B-H1069Q and revealed FDA-approved compounds as safe drugs for ATP7B mutant correction and, thus, for the normalization of Cu homeostasis in Wilson disease patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral