Human Diseases and Protein Folding: the Preservation of Biological Tasks - Book Report/Review Example

Introduction There are different means through which human beings are infected by varied disease processes. While some of these are environmental where various pathogenic organisms gain access to the human body and cause illness, some of these are genetic and are transferred from one generation to another through different processes. In particular these processes take place within the human body as a result of incorrect and dysfunctional processes. Some of these are normal and expected, whereas others are a result of the abnormal activities in the cells. This paper will be covering a major reason why despite the advances in technology to increase the life expectancy, there is an increased chance of acquiring degenerative and serious illnesses in old age. It will explain and outline reasons why there is a dramatic increase in the prevalence of degenerative illnesses among the elderly. The main emphasis will, however, be on the common features that originate from the family of protein deposition diseases (Bucciantini et, al., 2002, p. 509). Diseases that have been associated with protein misfolding have been depicted to be the result of their aggregation. This can either be out of chance, the effect of hyperphosphorylation of proteins, where additional groups of phosphate are added to the molecules of protein, through the self-catalyzing conformational conversion of prions or protein instability that results from varied mutations. In addition, aggregation can result from the increased intracellular levels of these proteins due to lack of regulation or pathological conditions. These will be supported by current research and studies that have been performed in this field. Role of Proteins in the Transfer of Genetic Material Proteins are an indispensable component of the human body since virtually all the basic cell functions are performed by proteins. They are essential for cell function since most chemical reactions and other structural components are supplied and mediated by the proteins. Proper folding and maturation of secretory and transmembrane proteins is known to take place in the Endoplasmic Reticulum (ER) (Austin 2009, p. 2280). The folding of the protein to form a native conformity occurs spontaneously before or after its biosynthesis. It, however, starts with a co-translational process whereby the N-Terminus is folded first while the C-terminus is still undergoing synthesis in the ribosome. This process depends on the presence or absence of molecular chaperons, the solvent molecules which ma comprise of water or a lipid bilayer, salt concentrations and temperature (Van der Berg 2000, p. 3873). For instance, high thermal temperatures, modification of pH and mechanical forces tend to denature the proteins. On the other hand, the molecular chaperons help the unstable proteins to find their configuration and achieve their native state hence enable proper folding using energy from ATP. A good example of this is the bacterial GroEL system that assists globular proteins in their folding (Lee & Tsai 2005, p. 260). They thus serve a vital role of helping them to fold correctly despite the fact that some of them still misfold. It is because they avoid the conformational changes that turn them into beta sheet structures and the aggregation of transformed proteins and hence act as fundamental components that work against the misfolding of proteins. They are also significant in preventing aggregation in cases of excessive heat or modified environmental conditions in the cells. Although most diseases are caused by pathogens such as viruses and bacteria, others result from the improper folding of proteins. Most living cells undergo protein unfolding. However, there are times that protein misfolding occurs. These misfolded proteins are mostly disposed off and eradicated by the Protein Quality Control (PQC) in young and energetic cells. The system detects the proteins and labels them to be transported to the cytoplasm for degradation as shown in Fig. 1. However, this load can be overwhelming for the PQC capacity in aging cells and those from individuals with predisposed genetic conditions. It ultimately leads to the risky accumulation of unfolded proteins. The associated diseases are caused due to aggregated misfolded proteins that turn into insoluble aggregates located extracellularly or intracellular inclusions in the form of beta sheets that are also known as amyloid fibrils. Fig.1: Degradation of misfolded proteins from the cell to the cytoplasm through the Unfolded Protein Response System and the Quality Control mechanism. http://www.nature.com/scitable/content/ne0000/ne0000/ne0000/ne0000/14463077/dobson_nature02261-f2.2_3_0.jpg Therefore, an impairment of the protein function is likely to cause devastating effects. In this relation, proteins play a very vital part in the multiplication and transfer of genetic material. It is relevant in explaining the process through which some human diseases are passed from the parents to their offspring due to genetic activity. The Process of Protein Misfolding During its formation and translation from an mRNA into linear chain amino acid sequence, each protein appears as an unfolded polypeptide or random coil. At this stage, it lacks an interactive three dimensional figure. In order for it to attain its functional shape or conformity later, it needs to undergo the folding process where its structure takes a distinct form. From a random coil, the polypeptide structure folds into a characteristic three dimensional form. This is achieved through interaction with other amino acid chains to form the folded protein or the native state of proteins that has its basic structure on the alpha helix (Alberts, 2002). It is the amino acid sequence that determines the resultant three-dimensional structure (Anfinsen 1972, Pp. 737-49). This functional or native state of proteins, which are not membrane bound, is water soluble. As indicated by Reynaud, synthesis on this native folded protein in healthy cells is a normal process that leads to the multiplication of protein molecules. However, at times genomes tend to code for inherently unstable proteins that fold in alternative areas where there is minimal energy state (2010, p. 28). It takes place when the proteins follow a wrong pathway while folding. Only a small number of these are functional hence useful to the cell since most of them are toxic. It is thus this misfolding of proteins that causes a different interaction of amino acid chains. As a result, there is a radical change in the protein despite the sequence on amino acids being the same. It undergoes extensive change in its conformation. It acquires the beta sheet conformation, which exposes amino acid residues that are hydrophobic and enhances the aggregation of proteins. It is for this reason that Berg, Tymockzo and Styrer assert that, for a protein to function normally, the three dimensional structure should be correct. This is despite the fact that some part of it usually remains unfolded (2002). Therefore, changes in the normal processes of protein folding and unfolding may lead to a great disparity between the original information and that transferred to the offspring. Whereas the modification and changes may not be significant, at times the slight alteration may result to serious disease development or death in extreme circumstances. Mutations, thermodynamic, as well as other external features, have a great influence in human health during the aging process. These, in turn, lead to the misfolding of proteins as they cause an imbalance and disturbance in relation to the processes through which proteins are synthesised, folded and degraded (Finkel 2005, p. 974). These may be caused by the mutagenic effect on the amyloidogenic gene through duplications, changes in the sequence of the amino acids on the protein chain or insufficient levels of proteosome, which is responsible for degradation of misfolded proteins. According to research, mutations that have adverse effects on protein folding largely interfere with the homeostasis in the ER leading to its stress. This is the extreme point reached when the cell’s capacity is overwhelmed by the folding process. However, the folding of proteins at times leads to allergies since the immune system in the human body lacks an antibody production system for certain proteins. Misfolded proteins are known to be insoluble and thus lead to the formation of long, linear fibrillar aggregates. Abnormal Events During the normal circumstances, the cell has set mechanisms that prevent the abnormal unfolding of proteins. It is the reason why at times, cell processes lead to the production of native conformations only. However, once in a while a random occurrence is experienced while millions of protein copies are being produced in the cell. A wrong path is followed by one of the proteins, which leads to the formation of a toxic configuration. It is a common occurrence in proteins that possess a repetitive amino acid motif. A proper example of this is the polyglutamine that causes Hunington’s disease. The toxic configurations are also referred to as infective conformations due to their ability to with native copies from the same protein. From this, they are able to catalyze them into the toxic state. These newly created toxic cells repeat the cycle of toxicity following a self- leading loop that leads to a disastrous effect that ultimately kills the cell and impairs its ability to function normally. Usually the prion proteins serve as the perfect examples of proteins that are able to catalyze and change their own conformational proteins into toxic forms (Uversky & Fink 2007, p. 135, 467). Relationship with Human Diseases These processes lead to a wide range of common neurodegenerative diseases as well as a number of diseases in human beings that include Alzheimer’s disease, spongiform encephalopathies and light chain amyloidosis (Uversky & Fink 2007, p. 3). They result from the production, deposition and accumulation of proteineceous aggregate tissues, which are known as amyloid fibrils and plaques that are formed from unfolded proteins. The other diseases caused by these conditions include cancer, Parkinson’s disease, Phenylketonuria, obesity and the two types of diabetes. Most of these are either Prion-related or Amyloid related illnesses that are associated with the aggravated proteins (Hammastron, Wiseman, Powers & Kelly 2003, p. 715). They are known to affect more than ten percent of the population that comprises aged individuals in different parts of the world. Nevertheless, they have been shown to be sporadic as they affect individuals without the association of family ties or presence of inherited characteristics. Moreover, these diseases are normally considered the result of the Unfolded Protein Response (UPR) by the human body. It is an integrated response to ER stress by the intracellular signalling pathway. It acts by creating an increased expression by the molecular chaperones in the ER-resident. It ensures that secretory proteins are folded using the correct machinery to manage the quantity needed by the cell. This, in turn, increases the overall protein translation and the degradation of unfolded proteins. If prolonged or acute ER stress is not managed, then the cell is likely to undergo apoptotic cell death. Numerous studies have revealed that it is the ER stress and activation of UPR that enhance the development and progression of such neurodegenerative diseases. Additionally, the capability of UPR to transform oxidative stress, apoptosis and inflammation offers important cellular information on how the cellular stress pathway is able to control both the normal physiologic processes, as well as the pathologic activities (Reynaud 2010, p. 28). Furthermore, oxidative damage to proteins is one of the external environmental factors that elevate the risks of acquiring degenerative diseases. It leads to the exposure of the mitochondria to substances that adversely affect it. An example is the basic form of Parkinson’s disease where the dominant varieties of the disease have been found to cause mutations. While a single production of the defective gene in the individual will result in disease development, two of the copies are required in the event that the gene is recessive. On the other hand, different forms of mutations on a single gene and combinations are required to exhibit diverse risks of diseases (Dobson 2002, pp. 729 & 730). Research has previously indicated that the fibril aggregates, which are closely identical to those related to clinical amyloidoses. They can be formed in vitro from proteins that are at times not associated with the diseases. As such, these aggregates of non disease causing proteins can become inherently cytotoxic (Bucciantini et, al., 20002, pp. 507-511). This takes place when the accumulated unfolded proteins are not degraded but are in the form of toxic oligomers and aggregates. The toxic functionality of proteins results when they fail to unfold and hence become modified inactive proteins. Contrary to this opinion, a recent study conducted by the European Medicines Agency confirmed that it is not the aggravate itself that leads to protein aggravation, protein homeostasis and protein turnover but the process through which the Amyloid fibrils are formed. Non neurological Diseases This apoptosis that is mediated by the ER-stress has, additionally, been widely linked to a large number of human diseases. They occur when specially designed cells in the body evolve to secrete proteins. It is because of this that effects of protein aggregation have also been identified to affect the peripheral system. These diseases express a protein that is not within its normal form that causes a transformation to a sticky non reversible configuration, which due to protein interactions results into rich beta sheets conformation. In this case, the kind of proteins involved is considered to be amyloidogenic. They are known to cause type 2 diabetes, some types of atherosclerosis, short chain amyloidosis and inherited cataracts. In the example of type 2 diabetes, there is a premature death of secretory cells. This case is known to occur when half of the islet beta cells in the pancreas die and result to the insufficient levels of insulin in the blood. These cells are specialized to produce and secrete insulin. It is speculated that the islet beta cells die as they try to fight the resistance of peripheral insulin that occur under obese conditions among those of over nutrition. It is this counteraction that results in their overwork that leads to an increased chronic ER stress. It is this circumstance that puts the cells at a high risk of apoptosis death, which is triggered by the UPR. The disease that sets in since as more cells die the remaining cells are subjected to extensive ER stress as they make efforts to handle more work than is recommended per cell. As such, it is a product of the vicious cycle created by these events. Infectious proteins The first incidence and suspicion on infectious proteins was established during the epidemic by a neurodegenerative disease that was known as kuru. It was discovered during the funeral practices that involve cannibalistic actions among the Fore Tribe. This population is found in Papua in the eastern highlands of New Guinea. The recognition of kuru as a prion disease led to the realization of the Creutzfeldt-Jacob disease as a neurodegenerative disease. It was found to originate from the ingestion of beef infected with toxic proteins although mutations also caused the conformational error in proteins (Reynaud 2010, p. 28). There has also been the concept of infectious protein which was revealed during research conducted on Scrapie. Its causative agent was believed to be a protein that destroyed nucleic acids since it was resistant to ultraviolet radiation (Alper, Haig & Clarke 1967, p. 765). Proteins such as prions were shown to be infectious when it was purified and shown to be the infectious agent on Scrapie. They thus dispelled the controversial topic that proteins could infectious (Prusiner 1982, pp 136-144). On the other hand, it has also been found out that the cellular effects that are brought about by the unfolding of proteins provide a basis for cell pathology. This, in turn, acts as a guide towards intervention and treatment of various genetic diseases, as well as those that are age-dependent (Gregersen 2006, p. 115). However, the severity of the diseases has according to research been shown to correlate with oxidative stress, dysfunction of the mitochondria, an alteration in the permeability of the cytoplasmic membrane, as well as abnormal concentration of calcium. This is illustrated in the table below Disease Genetic cause Function Alzheimer’s disease APP Leads to the production of Aβ, the basic component of senile plaques Parkinson’s disease Root is PS1 and PS2 It originates from Y-secretase and adheres to APP to secrete Aβ Parkinson’s disease α-Synuclein The basic element in Lewy components. Parkinson’s disease Parkin The ligase of ubiquitin E3 Parkinson’s disease DJ-1 Provides protection for the cell against death that is oxidant induced. Parkinson’s disease Caused by PINK1 A mitochondria localized kinase. Although its functions seem unclear, it is thought to protect the cell from death. Parkinson’s disease Originates from LRRK2 A kinase whose function is unknown. Parkinson’s disease HTRA2 It is a serine protease located within the intermembrane space in the mitochondria. It degrades the apoptosis protein inhibitors and is released into the cytosol to promote apoptosis. Amyotrophic lateral sclerosis SOD1 It leads to the conversion of superoxide to hydrogen peroxide. It seems to share associated functions with disease causing mutations. Hunington’s disease Huntingtin Its function is not yet known though mutations that are associated with diseases produce extensive polyglutamic repeates. Fig 2.: Lin & Beal 2006, p, 7690 It has also been found that misfolding together with excessive degradation lead to the development of several proteopathy diseases that include emphysema, which is associated with anti trypsin, lysosomal storage diseases and cystic fibrosis. The origin of the disease is identified as the loss of function. Summary It is revealed that although most globular proteins acquire their native state without the need for assistance, chaperone still plays an important role as they prevent aggregation in crowded intracellular environments. The related degenerative diseases have been shown to occur majorly due to aggregation of proteins as a result of misfolding. Protein therapy was previously used to correct the proteopathy disorders. However, research is currently underway to find ways to apply pharmaceutical chaperones that make mutated proteins functional by folding them. Conclusion In conclusion, human diseases associated with protein folding can be avoided by prevention of protein aggregation. This is because it is important in the preservation of biological tasks. However, the prospect of whether there is a chance in accumulation of the unfolded proteins lies in the properties of the specific proteins and the efficiency of the PQC systems in the individual. An essential suggestion is thus provided with regard to how the UPR system can be targeted to reduce human diseases. With the advent of technologies in RNA interference, precursors that are actively involved in the protein synthesis can be therapeutically inhibited. Numerous research and studies are underway to identify methods of chaperon induction, as well as mechanisms to inhibit hyperphosphorylation of proteins. Most of these diseases can also be prevented since they experience a long window within which their progression can be reversed. Finally, as suggested by Chiti and Dobson, vaccines are being developed against aggregation of proteins (2006, p. 360). It thus presents some ray of hope since there is currently no treatment for any of the Amyloid diseases. Bibliography Alberts, B., Alexander, J., Lewis, J., Raff, M., Roberts, K., & Walters, P., 2002. The Shape and Structure of Proteins: Molecular Biology of the Cell (4th Ed.). New York and London: Garland Science. Alper, T. Cramp, Haig, D. A., & Clarke, M.C., 1967. “Does the agent of scrapie replicate without nucleic acid?” Nature 214: 764–766. Anfinsen, C. (1972). "The formation and stabilization of protein structure". Biochemical Journal 128 (4): 737–49. Austin, C. Richard, 2009. “The unfolded protein response in health and disease”. Antioxidants redox signalling, Vol. 11(9): Pp. 2279-2287. Berg, M. J., Tymoczko, L. J., & Stryer, L: Web content by Neil D. Clarke, 2002. "3. Protein Structure and Function". Biochemistry. San Francisco: W. H. Freeman. Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, J., Ramponi, G., Dobson, C. M. & Massimo, S., 2002. “Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases”. Nature 416: Pp. 507 511. Chiti, F., & Dobson, C. M., 2006. Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry 75, 333–366. Dobson, C. M., 2002. Protein misfolding diseases: Getting out of shape. Nature 418, 729 730. Finkel, T., 2005. “Radical medicine: Treating ageing to cure disease”. Nature Reviews Molecular Cell Biology 6, 971–976. Gregersen, Niels, Bross, Peter, Vang, Soren, & Christensen, H. Jane, 2006. “Protein Misfolding and Human Disease”. Annual Review of Genomics and Human Genetics Vol. 7: Pp. 103-124. Hammarstrom, P., Wiseman, R. L., Powers, E.T., Kelly, J. W., 2003. “Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics”. Science, 299(5607): p. 713-716. Lee, S., & Tsai, F. (2005). "Molecular chaperones in protein quality control". Journal of. Biochemical and Molecular Biology 38 (3): 259–65. Lin, M. T. & Beal, M. F., 2006. “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases”. Nature 443, 787–795. Prusiner, S. B., 1982. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144. Reynaud, E., 2010. Protein Misfolding and Degenerative Diseases. Nature Education 3(9):28. Uversky, N. Vladimir, & Fink, L. Anthony., 2007. Protein misfolding, aggregation and conformational diseases. Part B, Molecular mechanisms of conformational diseases. New York: Springer. Van den Berg, B., Wain, R., Dobson, C. M., Ellis R. J.,August 2000. "Macromolecular crowding perturbs protein refolding kinetics: implications for folding inside the cell". EMBO Journal. 19 (15): 3870–5. Read More