A pharmaceutical researcher develops a therapy to treat a protein misfolding disorder. Specifically, a mutation in this disorder leads to abnormal protein folding and subsequent intracellular degradation of the protein before it can reach the cell membrane. With the new combination drug therapy, the first drug corrects the processing and trafficking of the protein, enabling it to reach the cell surface membrane. Once the protein has reached the cell surface, its function is enhanced by the second drug. This therapy is most likely to be helpful in which of the following conditions?

Question

A pharmaceutical researcher develops a therapy to treat a protein misfolding disorder.  Specifically, a mutation in this disorder leads to abnormal protein folding and subsequent intracellular degradation of the protein before it can reach the cell membrane.  With the new combination drug therapy, the first drug corrects the processing and trafficking of the protein, enabling it to reach the cell surface membrane.  Once the protein has reached the cell surface, its function is enhanced by the second drug.  This therapy is most likely to be helpful in which of the following conditions?

Quizplus · Accepted Answer

11ec160b_3788_665b_9249_7f3cead54d50_MD0001_00 Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) protein. ΔF508 is the most common CFTR gene mutation in patients with CF. This deletion causes abnormal protein folding and failure of glycosylation. The CFTR protein is then targeted for degradation by the proteasome before reaching the cell surface, causing an almost complete absence from the apical membrane of exocrine ductal epithelial cells. The rare CFTR proteins that do reach the cell membrane are abnormal, as the ΔF508 mutation also reduces channel opening. Lumacaftor and ivacaftor are CFTR-modulating medications that can potentially help patients with CF by restoring CFTR proteins to the membrane and also by enhancing protein function (eg, chloride transport) at the membrane, respectively. The combination of these 2 medications in patients with homozygous ΔF508 mutations has been shown to improve predicted forced expiratory volume (FEV) and decrease rates of pulmonary exacerbations. (Choice A) Polymorphisms in apolipoprotein E (APOE) are common in patients with Alzheimer disease (AD). The polymorphism leads to a conformational protein change that alters lipid binding, inhibits neurite growth, and leads to accumulation of amyloid-β, a peptide that aggregates in the brain in patients with AD. APOE is not a target of degradation or a transmembrane protein. (Choice B) Creutzfeldt-Jakob disease is a neurodegenerative disease caused by prions, which are contagious pathogens comprised of small, misfolded proteins that induce abnormal folding of normal proteins. Aggregates of misfolded proteins are difficult to degrade and result in apoptosis and neuronal loss. (Choice D) Phenylketonuria results from mutations in the hepatocyte enzyme phenylalanine hydroxylase. This enzyme is not normally transported to the cell surface. (Choice E) Sickle cell anemia results from mutations in the β-globin gene, leading to production of hemoglobin S, which can polymerize in states of low oxygen content. Hemoglobin S is not a transmembrane protein. Educational objective: ΔF508 is the most common mutation in the cystic fibrosis transmembrane regulator (CFTR) protein in patients with cystic fibrosis. This mutation leads to protein misfolding and failure of glycosylation, followed by proteasome-mediated degradation and significantly decreased number of transmembrane CFTR proteins. __________ References: Mechanisms of protein-folding diseases at a glance. (http://www.ncbi.nlm.nih.gov/pubmed/24396149) Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. (http://www.ncbi.nlm.nih.gov/pubmed/25981758) Advances in the diagnosis and treatment of cystic fibrosis. (http://www.ncbi.nlm.nih.gov/pubmed/25037130)

A Pharmaceutical Researcher Develops a Therapy to Treat a Protein