Protein Misfolding and Diseases | Homework Market Help

Introduction

Almost all biological functions in the cells of living organisms are usually performed by proteins, which are chain-polymers comprising of amino-acids synthesized on ribosomes according to the genetic information [1]. During protein synthesis, it is imperative for proteins to fold into distinctive 3-dimensional structures for them to be active biologically. In this regard, protein folding can be defined as the process by which protein molecules take up their functional conformation/shape, which often involves the polypeptide changing its shape from the random coil into its distinctive and functional 3-dimensional structure. The accurate 3-dimensional structure is a precondition for proteins to perform their biological roles; this implies that failure for a protein molecule to fold into its correct 3-dimesnional structure results in the production of toxic and inactive proteins [10]. Protein misfolding, which refers to the inaccurate folding and the clustering together of protein molecules, has been identified as one of the primary causes of diseases associated with aging such as Parkinson’s and Alzheimer’s disease and other degenerative diseases. The build-up of amyloid fibrils resulting from misfolded proteins has been proved to result in degenerative diseases. The goal of this paper is to discuss the importance of the 3-dimensional structure of proteins. The paper also discusses the concept of protein misfolding and discusses two diseases linked to protein misfolding. Lastly, the paper provides a discussion on the future of protein misfolding.

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The Importance of Protein Folding

Proteins are only helpful if they are functional, which is achieved by folding into its unique 3-dimensional structure. The production of proteins and how they attain their functional structure has been one of the mysteries in life sciences. The amino acids sequence in the protein usually determines the primary structure of the chain-like molecules [18]. Each protein molecule comprises of a unique sequence of amino acids joined together on a string by the ribosomes through a process referred to as translation [4]. The DNA information plays an integral role in determining the sequence of the amino acids in the protein molecule. In order to generate a protein, ribosomes usually read a duplicate of the respective DNA (messenger RNA), after which it translates the information into the amino acid sequence. However, a new-created protein molecule is useless biologically. For the protein chain to be functionally active, the newly created protein chain should fold into a unique 3-dimensional pattern.

Protein folding takes place when proteins chains begin to fold in particular places along the amino acid sequence that has non-polar groups, which often fold through aggregation, that is, the combination of a number of non-polar groupings. Deploying the same principle that separates water and oil, the molecules are hydrophobic in the sense that they associated with each other and avoid water. The figure is an illustration of how protein changes from an unfolded state to a folded state.

Figure 1: protein folding

Figure 2: Steps in protein folding

            External factors that such as molecular crowding, space limitations, external fields such as electric and magnetic fields, and temperature are likely to have a considerable influence on the protein folding process. Protein aggregation and misfolding is a significant problem because failure for a protein to fold accurately during synthesis or the protein misfolding in the course of its cellular life results in the cell ceasing to function biologically [18]. This can happen because of hereditary protein mutations that result in modifications of the amino acid sequence. An example is the case of cystic fibrosis caused by the removal of a single amino acid in the protein chain of Cystic Fibrosis Conductance Regulator (CFTR) [12]. The second danger arising from protein misfolding and aggregation relates to the toxicity of misfolded and aggregated proteins to living cells; this is because the deposits of misfolded protects tends to interfere with a number of cellular functions. The concept of protein misfolding offers a pathomechanistic understanding of several age-related illnesses associated with the nervous system such as the Parkinson’s and Alzheimer’s diseases, prion and Chorea Huntington diseases [18]. Research has shown that these neurodegenerative diseases are caused by the deposits of aggregated and misfolded protein molecules in either the brain or other parts of the nervous system. Diseases associated with protein misfolding are commonly associated with aging because of the decline in the protein quality control, as an individual grows older. Simply states, aging results in the body gradually losing its ability to stop the build-up of misfolded or aggregated proteins; this leads to a disastrous failure of protein homeostasis [11].

Protein Misfolding and Human Diseases

The relationship between protein misfolding and human diseases can be viewed from two perspectives, which includes neurodegenerative diseases and non-neurological diseases. With regard to the neurodegenerative diseases, it is apparent that the build-up of aggregated and/or misfolded proteins can result in human diseases commonly referred to as amyloid diseases such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. The occurrences of amyloid illnesses can be sporadic without any family history or hereditary factors and the risk of infection increases with an increase in age [10]. The explanation for this neurodegenerative diseases is that that as people age (or because of mutations), the delicate balance of protein synthesis, folding and degradation is disturbed, which leads to the production and build up of misfolded proteins in tissues of the nervous system. Protein misfolding disorders do not only affect the central nervous system but also other peripheral tissues. Examples of non-neurological diseases associated with protein misfolding include short-chain amyloidosis, hemadialysis-related disorders, atherosclerosis, and inherited cataracts among others. The general trend emerging from non-neurological diseases is the irregular tendency of protein molecules to clump together because of misfolding. The aggregation of protein molecules can be due to change; mutations that render the protein unstable; prion self-catalytic conformational conversion; or protein hyperphosphorylation, which is a condition characterized by several phosphate groups attached to the protein [1]. In aIDition, the aggregation of protein molecules can be due to a pathological increase in the intracellular concentration of specific proteins. Discrepancies with respect to protein concentration can also be attributed to mutations that alter the amino acid sequence, and proteasome deficiency, which a cellular machinery that plays an instrumental role in the degradation of aging [9].

Protein Misfolding and Alzheimer’s Disease (AD)

Alzheimer’s disease has been recognized as protein misfolding illness caused by the build-up of aggregated amyloid beta (A?) protein in the brain cells of patients. A? refers to a short peptide, which is a proteolytic by-product associated with the transmembrane protein amyloid precursor protein (APP). APP is hypothesized to play an instrumental role neurological development [1]. Despite the fact that A? monomers are nontoxic and soluble, they usually undergo a spectacular confrontational change when subjected to high cellular concentrations to form a tertiary protein structure that produces amyloid fibrils. The amyloid fibroids usually accumulate in neurons in the form of dense formations referred to as neuritic plaques, sometimes they form less dense aggregates referred to as diffuse plaques. In aIDition, they may accumulate in the walls of small blood cells found in the brain cells [8].

Alzheimer’s disease is also considered a tauopathy because of the irregular build-up of the tau protein, which is a microtubule-associated protein that usually stabilizes the microtubules found in the cytoskeleton. Just like other microtubule-associated proteins, the tau protein is usually regulated and controlled by phosphorylation [19]. However, in Alzheimer’s disease patients, the hyperphosphorylated tau usually build ups in the form of paired helical filaments, which in turn clump together into masses found inside nerve cells referred to as neurofibrillary tangles [7].

Despite the fact that the gross histological features of Alzheimer’s disease are well recognized, there are three main hypotheses relating to the disease mechanism and the primary cause of AD. The hypotheses include the cholinergic hypothesis, tau hypothesis and the amyloid hypothesis. With regard to the scope of this paper, we will focus on the tau hypothesis and the amyloid hypothesis [20]. The tau hypothesis draws on the observation that there is no correlation between the accumulations of amyloid plaques with neuron loss. The tau hypothesis suggests a mechanism for neurotoxicity basing on the decline of microtubule stabilizing tau protein, which results in cytoskeleton degradation [7]. Nevertheless, consent has not been reached regarding whether the tau hyperphosphorylation comes first or is it is caused by the production of anomalous helical filament aggregates. The empirical support for the tau hypothesis also stems from the fact that there are other illnesses referred to tauopathies, which are characterized by the misfolding of the same protein. However, biochemical researchers have supported the alternative hypothesis that asserts that the amyloid is the main causative agent of AD [6].

The amyloid hypothesis has received a lot of support from biochemical researchers regarding the causative agent of AD. The hypothesis is appealing owing to the fact that the gene for A? precursor APP is found in chromosome and patients suffering from Down syndrome (trisomy 21), who often have an aIDitional gene copy, tend to show signs of AD-like disorders by 40 years [19]. The conventional development of the amyloid hypothesis places emphasis on the cytotoxicity of mature clumped amyloid fibrils. The amyloid hypothesis provides a framework for drug development by inhibiting the fibrilization process. Early drug development research on lead compounds placed emphasis on this inhibition with most developed drugs reported to lessen neurotoxicity [5].

In terms of neuropathology, the protein misfolding processes in AD results in the loss of synapses and neurons in the sub cortical regions of the brain and the cerebral cortex. The outcome is that the affected regions are characterized by gross atrophy as well as the degeneration of the sections of the cingulate gyrus and frontal cortex, parietal lobe and temporal lobe [1]. Therefore, in AD, the build-up of A? in the hippocampus disturbs the complex neural networks of the brain, which leads to the loss of memory functions and death of cells. The neuropathology of AD is shown in the following figures 12, which shows the cross sections of both an AD and normal brain indicating the dramatic atrophy in the brain regions that are responsible for language and memory functions [18].

 

Protein Misfolding and Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease and its animal equivalents, the Mad Cow disease and the scrapie in sheep, are perhaps the most fascinating cases of protein folding disorders and have resulted in an uproar in the scientific community for several years. The prions, which are protein particles, are responsible for the transmission of the Creutzfeldt-Jakob disease. Prions are pure protein in the sense that they do contain neither RNA nor DNA [17]. How can a pure protein replicate itself? The answer to the mystery is gradually emerging and might be perceived as a variant with respect to the aspect of the pathological chaperone, whereby, only in this instance that the protein acts as its own chaperone. The body constantly produces the protein that aggregates to damage the nerve cells in Creutzfeldt-Jakob disease [16]. Usually, the protein folds correctly, is soluble and is often disposed without any problems. However, assume that a small amount of the protein misfolds in a given manner to produce a scrapie prion, if the scrapie prion comes in contact another protein that is folding normally, the scrapie protein tends to affect the folding process towards the direction of the misfolded scrapie protein regardless of the normal amino acid sequence of the protein. The process of affecting normally folding protein chains by scrapie misfolded proteins continues provided that the body continues to produce the normal protein. The scrapie prion will continue to replicate with the need to have a nucleic acid of its own [1]. The prion known to cause CJD exhibits two stable conformations. The first conformational state is soluble in water and often present in healthy cell. The second conformational state is water-soluble and plays an integral role in the formation of aggregates. CJD can also be acquired genetically when a gene responsible for coding the prion protein undergoes mutation. The CJD prion is extremely dangerous since it can result in protein refolding of the native proteins into an infectious state. In aIDition, the number of misfolded protein chains tends to increase exponentially, which results in a large number of insoluble protein aggregates in the affected brain cells.

There are three competing hypotheses that attempt to explain the underlying cause of Creutzfeldt-Jakob disease: the protein only hypothesis, multi-component hypothesis, and the viral hypothesis. The viral theory has been largely discredited. For the purposes and scope of this paper, the multi-component theory best explains the biochemistry of the Creutzfeldt-Jakob disease. According to the multi-component hypothesis, prions are likely to be more than just a protein although they lack a nucleic acid genome. A purified PrPC is not able to transform to the infectious PrPSc state unless other compounds such as lipids and RNA are aIDed [12]. The aIDed components, often referred to as co-factors are likely to constitute part of the infectious prion or that they may act as catalysts in the process of replicating the protein-only prion.

In the context of Creutzfeldt-Jakob disease, the misfolded proteins enter the brains and influence the normal proteins to misfold also damaging the brain cells [15]. This process is self-replicating, the dead brain cells produces more prions that get into other brain cells and destroys them further. Initially, the brain cells are destroyed which eventually damages the entire clusters of brain cells by damaging ad replacing the them with prion deposits referred to as plaques. Plaques create tiny holes in the brain that are sponge-like, which makes the brain to become full with holes. A sponge-like brain results in a damaged brain making the patient to show symptoms associated with the Creutzfeldt-Jakob disease [14].

The Future of Protein Misfolding

Currently, treatments to prevent specific problem misfolding disorders are being sought, especially with regard to interrupting the misfolding process and subsequent protein aggregation. For instance in the case of Alzheimer’s disease, treatments methods are being researched including the development of protease inhibiters aimed at stopping the A? release. In aIDition, drug developers are researching on ways that help break down the plaques and preventing the aggregation of A?. The challenge in developing treatment strategies for protein misfolding is identifying the ideal stage at which the protein misfolding and subsequent aggregation can be disrupted. It is also important for future treatment development to take into account the co-factors that influence protein misfolding and aggregation.

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