Misfolded Proteins

Humans have to deal with many different diseases and the ones most disliked are the ones with no cures. Like cancer, transmissible spongiform encephalopathies have no cure, but they are more rare. These diseases are prion diseases which cause the brain to deteriorate. Prions are proteins that sometimes behave like viruses, which mean that they should have some form of nucleic acid, but since they don’t, they cause abnormalities. The nervous system contains many normal prions, but when an abnormal prion comes along, it transforms all the normal prions into abnormal ones. Bovine spongiform encephalopathy is found in cattle, but it can be transmitted to humans.

Chaperones are proteins that ensure the correct folding of the CFTR within the endoplasmic reticulum. Hsp70 is an important cytosolic chaperone that complexes with CFTR and reduces aggregation [5]. The CFTR passes through the endoplasmic reticulum-associated degradation (ERAD) after folding in the ER. This quality control system involves the ubiquitin proteasome system (UPS) for which CFTR is a substrate [16]. If a protein is molded and targeted for degradation, then ubiquitin will covalently attach to lysine residues on the CFTR. Three enzymes are required for the process of ubiquitylation: E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, and E3 ubiquitin protein ligases. E1 enzymes are activated through hydrolysis of ATP, which creates an activated ubiquitin that is transferred to an E2 active site. The activated ubiquitin is then covalently bound to a lysine on the protein by an E3 ligase. A polyubiquitin chain is then formed as ubiquitin molecules link together, and if there are four or more then the misfolded CFTR chain is removed form the ER membrane and targeted for degradation by the 26S proteasome

In Seeds of Dementia, the authors, Larry C. Walker and Mathias Jucker, explain the ongoing search to understand more about dementia. The authors first credit the new way of thinking about dementia to the discovery of prions, which helped to confirm that dementia is transferrable through the sharing of brain matter. Prions, as proposed by Stanley B. Prusiner, are “proteins that [can] transmit disease”, and from this discovery comes the idea that we could “soon unify our thinking about how...diseases arise”. To further study the effect of prions on the brain, scientists injected Aβ plaques into mice to “determine whether extracts of brain tissue would initiate Aβ aggregation in the brains of mice”, and after experiencing positive results, the

It is a rare, degenerative but fatal brain disorder affecting very a small fraction of persons. The symptoms usually arise at the age of 60 and the person dies within a year. Many researchers believe that this disorder is the result of an abnormal protein known as prion. About 5-10% cases reported in the United States share a genetic basis where this form of dementia is caused by a mutation in the gene for the prion protein. Patients with Creutzfeldt-Jakob disease suffer from the problems associated with muscle coordination, personality changes, impaired memory, judgment making, thinking disability and impaired vision. Other possible symptoms include insomnia and depression. In later stages the persons

BSE is caused by the misfolded prion protein known as PrPsc which originated from PrPc protein. Prion proteins are formed when PrPc becomes a misfolded polypeptide chain – a change in the shape of the protein. PrPsc influences the folding of PrPc multiple times leading to aggregates to form fibers that

In recent years, studies have demonstrated that Aβ aggregates, as well as those of tau, can be inducible in a contagious, prion-like manner. Aβ rich extracts deposited into brains of APP-transgenic mice have been shown to diffuse from the region of inoculation to other, axonally connected regions. Notably, Aβ seems to require the presence of APP in brains, as in APP-transgenic mice for example, for this pathogenesis to occur. Tau, conversely, does not appear to need such a requirement. Studies show tau aggregates too propagate from injection sites to axonally connected regions even in non-transgenic (wild-type) mice (Jucker and Walker, 2011, 2013). Mutations in APP and presenelin (PSEN1/PSEN2) which have been identified in the inherited

The word BSE is short but it stands for a disease with a long name, bovine spongiform encephalopathy. "Bovine" means that the disease affects cows, "spongiform" refers to the way the brain from a sick cow looks spongy under a microscope, and "encephalopathy" indicates that it is a disease of the brain. BSE is a progressive neurologic disease of cows. Research shows that the first probable cases of BSE in cows occurred during the 1970 's with two cases of BSE being identified in 1986. BSE possibly originated as a result of feeding cattle meat-and-bone meal that contained BSE-infected products from a spontaneously occurring case of BSE or scrapie-infected sheep products. Scrapie is a prion disease of sheep. Similar diseases such as Chronic wasting disease which is in both deer and elk populations is devastating the hunting and the reproduction of deer. Other similar disease such a the Creutzfeldt-Jakob disease which occurs in the human body system. That is pretty scary for us humans. We have got to find a way to get this prion settled down and hopefully I can show you the way the scientist plan to get rid or at least slow it down. There is strong evidence and general agreement that the outbreak was then amplified and spread throughout the United Kingdom cattle industry by feeding rendered, prion-infected, bovine meat-and-bone meal to young calves. A lot of people wander what does it to the consumption of the meat does it ruin it or is it ok to eat? What does the meat that

The infectious agent in BSE is accepted to be a particular sort of misfolded protein called a prion. Prions won't vanish regardless of the fact that the meat containing them is cooked. Prion proteins convey the ailment in the middle of people and cause crumbling of the cerebrum.

Though a relatively new institution, the realm of public health has been fairly consistent from its conception. Using a methodology centered in evidence-based, population-approach health studies, scientists have been given the means to fight and control disease around the world. Traditionally, a communicable disease is caused by one of three foreign agents: bacteria, parasites, viruses. While quite different, these four agents have much in common, including their adherence to Koch’s germ theory, their reliance on human hosts, and methods of transmission. In the last twenty years or so, however, the scientific community has encountered a fifth type of pathogen that is completely different in size, composition, and the disease it causes – the prion. In its simplest form, a prion is a protein in a misfolded form. Essentially, this protein propagates by transmitting its misfolded state to other proteins in its host, specifically in cranial and neural tissue. The altered structure of the protein, which constitutes the prion, is extremely stable, and cannot be denatured by chemical and physical agents. The harm comes to the human or animal when the prions aggregate extracellularly in the central nervous system, creating plaques and holes in the tissue - diseases that are caused by prions are known as transmissible spongiform encephalopathies (TSEs). The recent discovery of prions, though rare in existence, pose a serious threat to the consistency of public health and the

Neurodegenerative diseases are progressive disorders that mainly affect neuronal cells and functions, and commonly characterized by abnormal protein metabolism and aggregations i.e. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, Prion diseases, Motor neurone disease, Amyotrophic lateral sclerosis (ALS), Lou Gehrig’s disease, among others. Currently, there is no single cure out there to treat these debilitating diseases. However, present therapies available either slow down the disease progression or inhibit mutant protein’s aggregation. Recent studies are facilitating our understandings in both neurochemistry and the genetic pathogenesis of the disease nature, which may result in exciting new discoveries and also provide a platform for the development of new effective drugs to cure these devastating diseases. This essay will discuss the shared pathological characteristics for common therapeutic approaches to combat against these incapacitating diseases with particular focus on the two most common neurodegenerative diseases: Alzheimer’s and Parkinson’s disease.

The cellular functions of chaperones are vital to all living organisms from prokaryotes to man. Molecular chaperones are stress proteins that are involved in inhibition of protein aggregation and that participate in numerous normal cellular processes such as protein folding, assembly, and transportation of secretory or transmembrane proteins. A newly synthesized polypeptide chain must fold to its energetically stable, native, tertiary or

Chaperonins are one our of the two types of chaperones that assist in protein folding. It does not actually participate in protein folding, but isolates aggregated protein from other compounds to be able to interact with its individual strand. It provides a stable environment that ensures proper folding. The protein comes in contact with the Gro-EL-GroES complex that has a bullet or a symmetrical football shaped complex. Here, the intermediate folding of protein is activated.

This discovery in biology was something astonishing and Prusiner earned the 1997 Nobel Prize from it. Prusiner then called this “prion protein” or PrP, although it turned out that everyone has this protein, even those who aren't sick with the disease. The question in concern was how did people have prion protein but weren’t getting sick with a prion disease. So, normally PrP come in a healthy state called “cellular prion protein” or PrPC. Although if the protein is misfolded then it can turn into “scrapie prion protein” or PrPSc and one of these particles can convert a PrPc (cellular prion protein) into a scrapie prion protein (PrPSc). “PrPSc is like ice-nine: it “teaches” the other prion proteins how to fold up into a disease state [Kocisko 1994].”( What are prions?). These prion proteins usually clump together to kill brain cells and can lead the brain to have holes. The holes in the brain cause it to look sort of spongy therefore they named this certain disease, Transmissible Spongiform Encophilothophei

The protein misfolding induces structural conversion of a soluble protein to insoluble amyloids through self-assembling. The protein aggregation induces the loss of biological function and gain of disease and is well connected to several diseases such as neurodegenerative disorders, prion diseases and type-II diabetes. Several studies have been carried out to elucidate the role of protein misfolding and aggregation in the pathogenesis of a number of protein conformational diseases (ref). Among several conformational diseases, the Alzheimer’s disease (AD) has been studied to a wide extent from decades, and a recent study estimated 5.5 million Americans are living with this fatal disease (ref). It also has been estimated (World Alzheimer

Molecular chaperones stabilize unfolded or misfolded proteins until native conformations have been obtained to promote cell survival during and after stress conditions. They do not change or add to the folding principles encoded by a protein because polypeptide chains inherently carry within them all the information that is necessary for achieving the native state of a protein. Instead, they optimize the folding process by stabilizing folding intermediates and are involved in every aspect of proteome maintenance including de novo folding, refolding of stress-induced misfolded proteins, and targeting proteins for degradation (Hartl 2009, Hartl 2011). Chaperones, many of which are induced or upregulated only during stress conditions, work in cooperative networks when protein-aggregate concentration