The Relationship Between Protein Misfolding and Human Diseases

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Folding and unfolding of proteins are crucial factors which determine the biological activity and targeting to various cellular locations (Vendruscolo et al., 2003). Synthesis of various proteins is initiated by ribosomes through the cellular information contained in the DNA. Formation of proteins begins by synthesis of amino acids and the process in which the amino acids transform is described as protein folding (Hardesty and Kramer, 2001). Protein folding depends upon multiple contributing and intrinsic properties of amino acids and forms the basis of many cellular functions. One of the most common mechanisms which are prevalent in many diseases is the aggregation of misfolded proteins escaping the quality control measures of the cell (Vendruscolo et al., 2003). The relative thermodynamic and kinetic properties are responsible for the interconversion of folding and misfolding states. These conversions are highly regulated by proteolytic enzymes, molecular chaperones and environment and the failure of the regulation is main cause for protein misfolding and diseases associated with it (Dobson, 2004).

Figure 1: Depiction of Amyloid fibril with a representation of its highly misfolded structure (Adapted from Dobson, 2004)

In relation to protein misfolding and the diseases associated with it, there are many exciting approaches which are being developed based on the understanding of misfolding and the changes of cellular mechanisms which are responsible for it (Dobson, 2004). One of the recent developments regarding the scope of protein misfolding in diseases is the proposal by National Institute on aging (NIA) whose main responsibility is to support research on the effect of aging on cardiovascular, musculoskeletal, immune, nervous and sleep syndromes. NIA supports the development of assays to screen molecules for determining efficacy in these diseases due to protein mis-processing, mis-targeting and misfolding (National Institute on Aging, 2010).


Research done on diseases caused by protein misfolding:

There is little knowledge on the pathological behaviour of diseases in relation to protein misfolding however many recent studies have shown the influence and relation of protein misfolding in diseases. In systemic diseases, the main cause of pathology is related to the sheer mass of insoluble proteins which disrupts the physiological function of the organs or the loss of major functional proteins which causes subsequent failure of crucial cellular mechanisms (Pepys et al., 1995). In the cases of neurodegenerative syndrome like memory disorders and Alzheimer’s disease, the main cause of pathology is attributed to destruction of neurons by toxic gain function caused by protein misfolding and aggregation. Most of the studies also revel that the early prefibrillar aggregates of proteins are more damaging when compared to the mature fibrils in the neurological diseases. Some of the studies also indicated that the shape of the aggregates caused by protein misfolding also results in ionic imbalance indirectly contributing to the pathology of cells (Caughey and Lansbury, 2003). For Example, the aggregates which look similar to bacterial toxin form the major cause of ionic disruption in neurodegenerative disorders. Various questions have been raised about the tolerance of incompletely folded proteins to get aggregated in to resembling structures (Ellis, 2003). Many of the researches have answered that the chaperones and other cleaning mechanisms efficiently ensure that the toxic species are neutralised upon release under normal circumstances. There are various types of chaperones which convert the precursors of Amyloid fibres in to normal intractable species which makes them refoldable to normal amino acid chains which can later be disposed into degradable systems (Caughey and Lansbury, 2003). One of the evidences explaining the system includes the role of polyglutamine sequences in Huntington’s disease where the precursors of the misfolded fibres convert back into amorphous species by the aid of molecular chaperones. However in some cases, these protective mechanisms fail to exhibit their activity which forms the main cause of potentially harmful species to sequester with harmless bodes causing the major pathological intervention (Dobson, 2001).

In the synthesis of proteins, there are several steps through which folding and unfolding takes place (David, 2003). The control of these processes is regulated by chaperones which aid in adapting functional and physiological conformations which are essential for normal body activities. Many intermediates are involved in the synthesis of proteins which are depicted in figure 2. There are numerous stimuli which control the process including mutation, induction of oxidation and production of free radicals which leads to misfolding of proteins. The cell responds to these responses by unfolded protein response (UPR) and ubiquitin-proteasome system (UPS) (David, 2003). Excessive function of these responses leads to cellular degeneration.

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Figure 2: Depiction of flow cart elucidating the folding and misfolding of the protein (Adapted from David, 2003).

Most of the diseases are caused by tendency of aggregation unless the environment is tightly regulated. Random mutations act as another major cause for instability in the proteins causing interconversion between the two distinct forms of folded and misfolded structures. Alzheimer’s disease and neurological syndromes are some of the examples caused due to mutations leading to misfolding of the diseases (Dobson, 2004). Ageing also forms another devastating factor for protein aggregation and misfolding due to weakening of house keeping ...

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