Molecular Bases of Disease
A potential strategy for reducing cysts in autosomal dominant polycystic kidney disease with a CFTR corrector
Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of cysts, leading to a decline in function and renal failure that cannot be prevented by current treatments. Mutations in pkd1 and pkd2, encoding the polycystin 1 and 2 proteins, induce growth-related pathways, including heat shock proteins, as occurs in some cancers, raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. Here, we demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR), conventionally used to manage cystic fibrosis in reducing renal cyst growth.Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2+ channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD.Combination of Correctors Rescue ΔF508-CFTR by Reducing Its Association with Hsp40 and Hsp27
Background: Mutations in nucleotide binding domain 1 of cystic fibrosis (CF) transmembrane conductance regulator cause severe CF.Results: Correctors rescue trafficking of ΔF508 by altering interaction with Hsp27 and −40.Conclusion: Rescue of trafficking mutants can be accomplished by combining correctors from different classes.Significance: ΔF508 is the most common mutation. Information on the mechanism of corrector action is critical for treating the majority of patients.Rescuing Trafficking Mutants of the ATP-binding Cassette Protein, ABCA4, with Small Molecule Correctors as a Treatment for Stargardt Eye Disease
Background: Mutations in nucleotide binding domain 1 of ABCA4 cause Stargardt Disease.Results: Correctors rescue trafficking of NBD1 mutants by altering a proteostatic network of quality control proteins.Conclusion: Rescue of trafficking ABCA 4 mutants can be accomplished by correctors similar to CFTR.Significance: There is currently no treatment for Stargardt macular degeneration.
