ERAD In Cystic Fibrosis: A Literature Review

What is Cystic Fibrosis? How does it affect people living with it? Cystic Fibrosis, also known as CF, is a life-threatening hereditary disease. It is inherited by a faulty cystic fibrosis transmembrane conductor (CFTR) gene from each parent (Kowalczyk, 2014, p. 74). This faulty gene makes a defective protein that does not work well and causes the body to produce sticky, thick mucus and very salty sweat("About CF: Causes, Signs & Symptoms of Cystic Fibrosis,"

The pancreas produces insulin and makes proteins that process sustenance. In Cystic Fibrosis patients, the thick sticky bodily fluid is delivered, obstructs the conduits of the pancreas, diminishing the creation of insulin and keeping digestive chemicals from achieving the guts to help absorption. At the point when this happens, patients can have ceaseless the runs, hunger, poor development and weight reduction. In their puberty or even adulthood, patients with Cystic fibrosis can create cystic-fibrosis related diabetes mellitus (CFRDM) because of the deficiency of insulin. Cystic fibrosis was once viewed as a lethal sickness in influenced patient's youth, yet with enhanced and new medications, better administration of the infection, and on-going examination, patients with Cystic fibrosis are living great into adulthood. Consistently, 1,000 youngsters with cystic fibrosis (CF) are conceived in the United States. One in 3,000 Caucasian babies has the confusion, making CF a standout amongst the most widely recognized deadly hereditary sicknesses in

I couldn’t imagine what it would be like growing up with a life threating condition that has no cure. Amanda Estep is a 21-year-old, college student and also a close friend of mine who has been battling Cystic Fibrosis since she was three years old. Cystic Fibrosis is a genetic condition that causes mucus to build up in the lungs and digestive system, making it hard to breath. “Basically everything in my body is thicker, so the mucus in my lungs is harder to break up and get out which causes frequent lung infections.” Amanda explained to me. Cystic Fibrosis also impacts her ability to digest food, resulting in her being underweight most of her life. While I have known Amanda since kindergarten, we have never talked in depth about how much she has to do to remain as healthy as possible. Hearing her explain her story made me realize how lucky I am to be healthy, and that’s something’s no one should take for granted. There is currently no cure for Cystic Fibrosis, but Amanda shared some of the many things she has to do in order to remain as healthy as possible. Some of those things includes being hospitalized for two weeks four or five times a year, taking many medications, and knowing how hard she can push herself.

Cystic fibrosis is an inherited disorder that causes severe damage to the lungs and digestive system. This disorder is among over 70,000 people worldwide, and about 30,000 just in the United States alone. Nearly half of the Cystic Fibrosis population is age 18 or older, and are normally diagnosed by age 2. Though Cystic fibrosis is a complex disease and the types and severity of symptoms can differ widely from person to person. Many different factors, such as age of diagnosis, can affect an individual's health and the course of the disease. Today the median survival age for having this disorder is close to 40 years old. To most that might seem very young, but this is a huge improvement from what it was in past years. New advances in technology makes it possible for people with this disorder to

Cystic Fibrosis is a genetic disorder that cause very serious damage to the lungs and also the other parts of the digestive system. Cystic fibrosis affects the cell in other ways like harming the cell that produces mucus, sweat and also digestive juices. The are normally thin and glossy so that makes it very slippery. In people with CF, a defective gene causes a thick, buildup of mucus in the lungs, pancreas and other organs. In the lungs, the mucus clogs the airways and traps bacteria leading to infections, extensive lung damage and eventually, respiratory failure. In the pancreas, the mucus prevents the release of digestive enzymes that allow the body to break down food and absorb vital nutrients. People with cystic fibrosis are at greater risk of getting lung infections because thick, sticky mucus builds up in their lungs, allowing germs

There are many treatments to help with keeping people healthy and extending the life expectancy for this disease. One of the treatments

Cystic fibrosis (CF) is an inherited autosomal recessive disorder that affects the lungs and digestive system most often. In the United States some 30,000 children and adults have CF. There are approximately 1,000 new cases of cystic fibrosis diagnosed each year in the US with 70% of patients diagnosed with CF by the age of two, 40% of patients with CF are 18 or older. In the 1950's most children with CF did not survive to attend elementary school, but in 2006 the median age of survival was 37 years (Cystic Fibrosis Foundation, 2007).

The discovery of therapeutic molecules that target the underlying cause of Cystic Fibrosis, rather than the symptoms, has transformed the approach of cystic fibrosis treatments. Two such sets of drugs are classed as correctors and potentiators. The latter set aim to target and augment the function of the mutated CFTR channel that is present on the membrane. Class III and IV CFTR mutations benefit from this approach as they are defined as mutated CFTR channels that, although present on the apical membrane, exhibit decreased, or no functional activity compared to functional CFTR channels. Class III mutations are missense mutations that result in a reduce open time of the CFTR channels. This severe class of mutations include G551D and S549R

Cystic fibrosis, an inherited disease of the secretory glands that affects the liver, pancreas, intestines, lungs, sinuses, and sex organs, affects about 30,000 Americans with 1,000 new cases diagnosed each year. Normal mucus is a watery, slick substance made by the tissues that keeps the inside of organs moist, preventing infection. People with cystic fibrosis have thick and sticky mucus that builds up in their lungs, blocking the airways. This buildup can cause serious lung diseases from bacteria growth that damages the lungs. This damage to the lungs can cause severe breathing problems which can lead to respiratory failure. Respiratory failure is the most common cause of death in people with cystic fibrosis. The thick and sticky mucus also can block the tubes that carry important enzymes from the pancreas to the small intestines that are needed to break down food and for your body to absorb the nutrients essential for one’s health.

Cystic Fibrosis is a recessive disorder that is a life threatening disease that causes persistent lung infections and progressively limits the ability to breath. Unfortunately, there is no cure for this genetic disorder, but Airway Clearance, Inhaled Medicines, and Pancreatic enzyme supplements can increase the person’s lifespan incredibly. There are about 70,000 people worldwide with this disease. Approximately 1,000 new cases of cystic fibrosis are diagnosed each year. The average human with cystic fibrosis lives to about 30 if they take their medicine.

The disease starts because the 7th chromosome that makes a protein called Cystic Fibrosis Transmembrane Regulator or CFTR has mutated and now the body produces to much of the protein

This protein is in charge of the movement of water and sodium ions through channels, giving substances like mucus a thick or thin concentration by moving the substances through the channels as needed (Cystic Fibrosis, 2015). Though it is known as a gene that can cause cystic fibrosis, it is not the only condition that can be a result of this mutation and if a mutation is found on this gene it is not a definite result that the child will have CF and will need further testing in order to determine what the physical manifestation of the mutation will be (Cystic Fibrosis,

There are several theories states that how the defects in the protein and cellular function causes the clinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body 's immune system. Another theory is that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory is that abnormal chloride movement out of the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc.

Soluble misfolded proteins are generally regulated by autophagy while insoluble misfolded proteins are primarily targeted by ubiquitination and removed by proteasomes. TDP-43 and SOD1 aggregates form insoluble clusters in the cytoplasm (Keskin et al., 2016; Neumann et al., 2006; Parakh et al., 2016; Pickles et al., 2016; Pokrishevsky et al., 2012). Conversely, studies have shown that wild type SOD1 is less soluble than the misfolded SOD1, and the more soluble the misfolded protein is from the mutation, the more toxic the misfolded SOD1 becomes for the cell (Brotherton et al., 2013; Xu et al., 2014). Furthermore, soluble misfolded SOD1 has a significant affinity for the mutant SOD1 variants, which may present a mechanism for increased toxicity in sporadic ALS patients (Xu et al., 2014). This suggests that soluble misfolded SOD1 associates with SOD1 aggregates, and could cause further mislocalization and accumulation of mutant SOD1. Surprisingly, when mutant SOD1 was co-expressed with wild-type SOD1 it become more toxic, suggesting that the wild-type SOD1 enhanced the toxicity of the mutant SOD1 (Brotherton et al., 2013). Mutant SOD1 variants were placed in lysates of fibroblasts with inhibited proteasome and autophagy. The misfolded SOD1 proteins greatly increased toxicity with the proteasome inhibited (Brotherton et al., 2013; Keskin et al., 2016), while the opposite was true for the autophagy inhibited fibroblasts (Keskin et al., 2016). This suggests protein digestion of

Recently, two strains of human SOD1 were isolated and expressed in transgenic mouse models, which resulted in ALS progression accompanied by the propgation of the SOD1 aggregates from the spinal cord to the brainstem (Bidhendi et al., 2016). Additionaly, several studies have identified a Q/N-rich prion-like domain in the TDP-43 C-terminal sequence composed of glutamate and aspartate rich regions that are susceptible to aggregation (Bozzo et al., 2016; Cirulli et al., 2015; Kitamura et al., 2016; Wei, Yuanyuan et al., 2016). Cleavage of TDP-43 prion-like domain yields a truncated TDP-25 fragment that is less prone to aggregation when accompanied with TDP-25 stabilizing RNA binding proteins (Kitamura et al., 2016). Multiple studies have concluded that mutant and wild type SOD1 aggregates can seed cytoplasmic inclusion bodies in healthy neurons (Münch et al., 2011; Polymenidou et al., 2011; Smethurst et al., 2016; Walker & Jucker 2015). TDP-43 aggregates have also displayed similar behivior of cell-to-cell propogation in vitro (Nonaka et al., 2013; Polymenidou et al., 2011; Walker & Jucker 2015; Wei, Yuanyuan et al., 2016). This suggests that both SOD1 and TDP-43 misfolded proteins seed aggregation and ALS propogtion that infects adjacent cells. However, the primary method of SOD1 and TDP-43 prion-like propgation has still not been fully elucidated.