Pharmacological correction of misfolding of ABC proteins

Rudashevskaya, Elena L.; Stockner, Thomas; Trauner, Michael; Freissmuth, Michael; Chiba, Peter

doi:10.1016/j.ddtec.2014.03.009

Cited by 16 publications

(20 citation statements)

References 43 publications

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“…It has been hypothesized that if the cellular environment can be altered, the CFTR protein defect may be bypassed. One of the ways to approach this is by improving proteostasis in CF cells [42–44]. Proteostasis improvement helps to re-establish the plasma membrane localization of CFTR.…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

et al. 2016

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BackgroundThe airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well as a distinct microbiota. Pseudomonas aeruginosa is recognized as one of the most important pulmonary pathogens and the predominant cause of morbidity and mortality in CF. A multifarious interplay between the host, pathogens, microbiota, and the environment shapes the course of the disease. There have been several excellent reviews detailing CF pathology, Pseudomonas and the role of environment in CF but only a few reviews connect these entities with regards to influence on the overall course of the disease. A holistic understanding of contributing factors is pertinent to inform new research and therapeutics.DiscussionIn this article, we discuss the deterministic alterations in lung physiology as a result of CF. We also revisit the impact of those changes on the microbiota, with special emphasis on P. aeruginosa and the influence of other non-genetic factors on CF. Substantial past and current research on various genetic and non-genetic aspects of cystic fibrosis has been reviewed to assess the effect of different factors on CF pulmonary infection. A thorough review of contributing factors in CF and the alterations in lung physiology indicate that CF lung infection is multi-factorial with no isolated cause that should be solely targeted to control disease progression. A combinatorial approach may be required to ensure better disease outcomes.ConclusionCF lung infection is a complex disease and requires a broad multidisciplinary approach to improve CF disease outcomes. A holistic understanding of the underlying mechanisms and non-genetic contributing factors in CF is central to development of new and targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

et al. 2016

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“…In recent years, reports have surfaced regarding pharmacological approaches to correcting misfolding of a subfraction of proteins in the secretory pathway, including mutant enzymes, receptors, transporters, and ion channels (38), such as the cystic fibrosis transmembrane regulator (39), ATP-binding cassette transporters (40), gonadotropin-releasing hormone receptor (41), superoxide dismutase 1 (42), lysosomal enzymes like β-glucosidase (43), and others. Pharmacotherapies are beginning to be reported that can ameliorate ER stress in pancreatic β-cells as well (44–47); however, no pharmacotherapies that specifically help correct proinsulin misfolding in the ER have yet been reported.…”

Section: Discussionmentioning

confidence: 99%

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

et al. 2016

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Proinsulin folding within the endoplasmic reticulum (ER) remains incompletely understood, but it is clear that in mutant INS gene–induced diabetes of youth (MIDY), progression of the (three) native disulfide bonds of proinsulin becomes derailed, causing insulin deficiency, β-cell ER stress, and onset of diabetes. Herein, we have undertaken a molecular dissection of proinsulin disulfide bond formation, using bioengineered proinsulins that can form only two (or even only one) of the native proinsulin disulfide bonds. In the absence of preexisting proinsulin disulfide pairing, Cys(B19)-Cys(A20) (a major determinant of ER stress response activation and proinsulin stability) preferentially initiates B-A chain disulfide bond formation, whereas Cys(B7)-Cys(A7) can initiate only under oxidizing conditions beyond that existing within the ER of β-cells. Interestingly, formation of these two “interchain” disulfide bonds demonstrates cooperativity, and together, they are sufficient to confer intracellular transport competence to proinsulin. The three most common proinsulin disulfide mispairings in the ER appear to involve Cys(A11)-Cys(A20), Cys(A7)-Cys(A20), and Cys(B19)-Cys(A11), each disrupting the critical Cys(B19)-Cys(A20) pairing. MIDY mutations inhibit Cys(B19)-Cys(A20) formation, but treatment to force oxidation of this disulfide bond improves folding and results in a small but detectable increase of proinsulin export. These data suggest possible therapeutic avenues to ameliorate ER stress and diabetes.

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“…For patients with specific mutations in ABCB11 (primarily miss-sense mutations), the basic transporter defect may be (partially) overcome by chaperones/small molecule strategies (e.g., 4-phenybutyrate and glycerol phenylbutyrate) that promote protein folding and enhance the functional expression of transport proteins in the liver [104]. Inhibition of intestinal bile acid absorption is being investigated as an alternative approach to treat these diseases.…”

Section: Progressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

Biliary atresia and other cholestatic childhood diseases: Advances and future challenges

Verkade

Bezerra

Davenport

et al. 2016

Journal of Hepatology

141

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Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

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Pharmacological correction of misfolding of ABC proteins

Cited by 16 publications

References 43 publications

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

Biliary atresia and other cholestatic childhood diseases: Advances and future challenges

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