Protein Misfolding and Aggregation as a Cause of Disease
editThrough the transcription and translation process, DNA encodes for specific sequences of amino acids. The resulting polypeptides fold into more complex secondary, tertiary, and quaternary structures to form proteins. Based on both the sequence and the structure, a particular protein is conferred its cellular function. However, sometimes the folding process fails due to mutations in either the genetic code or the amino acid sequence or due to changes in the cell environment (e.g. pH, temperature, reduction potential, etc.). Misfolding occurs more often in aged individuals or in cells exposed to a high degree of oxidative stress, but a fraction of all proteins misfold at some point even in the healthiest of cells.
Normally when a protein does not fold correctly, molecular chaperones in the cell can encourage refolding back into its active form. When refolding is not an option, the cell can also target the protein for degradation back into its component amino acids via proteolytic, lysosomal, or autophagic mechanisms. However under certain conditions or with certain mutations, the cells can no longer cope with the misfolded protein(s) and a disease state results. Either the protein has a loss-of-function, such as in cystic fibrosis, in which it loses activity or cannot reach its target, or the protein has a gain-of-function, such as with Alzheimer’s disease, in which the protein begins to aggregate causing it to become insoluble and non-functional.
A common form of aggregation is long, ordered spindles called amyloid fibrils which are implicated in Alzheimer’s disease which have been shown to consist of cross-linked beta sheet regions perpendicular to the backbone of the polypeptide[1]. Another form of aggregation occurs with prion proteins, the glycoproteins found with Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. In both structures, aggregation occurs through hydrophobic interactions and water must be excluded from the binding surface before aggregation can occur[2]. A movie of this process can be seen in "Chemical and Engineering News"[3]. The diseases associated with misfolded proteins are life-threatening and extremely debilitating which makes them an important target for chemical biology research.
Protein misfolding has previously been studied using both computational approaches as well as in vivo biological assays in model organisms such as Drosophila melanogaster and C. elegans. Computational models use a de novo process to calculate possible protein structures based on input parameters such as amino acid sequence, solvent effects, and mutations. This method has the shortcoming that the cell environment has been drastically simplified which limits the factors that influence folding and stability. On the other hand, biological assays can be quite complicated to perform in vivo with high-throughput like efficiency and there always remains the question of how well lower organism systems approximate human systems.
Dobson et al. propose combining these two approaches such that computational models based on the organism studies can begin to predict what factors will lead to protein misfolding[4]. Several experiments have already been performed based on this strategy. In experiments on Drosophila, different mutations of beta amyloid peptides were evaluated based on the survival rates of the flies as well as their motile ability. The findings from the study show that the more a protein aggregates, the more detrimental the neurological dysfunction [4][5][6]. Further studies using tranthyretin, a component of cerebrospinal fluid which binds to beta amyloid peptide deterring aggregation but can itself aggregate especially when mutated, indicate that aggregation prone proteins may not aggregate where they are secreted and rather are deposited in specific organs or tissues based on each mutation[7]. Kelly et al. have shown that the more stable, both kinetically and thermodynamically, a misfolded protein is the more likely the cell is to secrete it from the endoplasmic reticulum rather than targeting the protein for degradation.[8] Additionally, the more stress that a cell feels from misfolded proteins, the more probable new proteins will misfold[9]. These experiments as well as others having begun to elucidate both the intrinsic and extrinsic causes of misfolding as well as how the cell recognizes if proteins have folded correctly.
As more information is obtained on how the cell copes with misfolded proteins, new therapeutic strategies begin to emerge. An obvious path would be prevention of misfolding. However, if protein misfolding cannot be avoided, perhaps the cell’s natural mechanisms for degradation can be bolstered to better deal with the proteins before they begin to aggregate[10]. Before these ideas can be realized, many more experiments need to be done to understand the folding and degradation machinery as well as what factors lead to misfolding. More information about protein misfolding and how it relates to disease can be found in the recently published book by Dobson, Kelly, and Rameriz-Alvarado entitled Protein Misfolding Diseases Current and Emerging Principles and Therapies[11].
References
edit<references>
- ^ Jordens, S., Adamick, J., Amar-Yuli, I., and Mezzenga, R. (2010) Disassembly and Reassembly of Amyloid Fibrils in Water−Ethanol Mixtures, In Biomacromolecules, ACS Publications. DOI:http://dx.doi.org/10.1021/bm101119t
- ^ Reddy, G., Straub, J. E., and Thirumalai, D. (2010) Dry amyloid fibril assembly in a yeast prion peptide is mediated by long-lived structures containing water wires, Proceedings of the National Academy of Sciences of the United States of America 107, 21459-21464. DOI: http://dx.doi.org/10.1073/pnas.1008616107
- ^ Borman, S. A. (2010) Water Factors In On Amyloid And Prion Aggregation Rates, In Chemical and Engineering News, ACS Publications
- ^ a b Luheshi, L. M., Crowther, D. C., and Dobson, C. M. (2008) Protein misfolding and disease: from the test tube to the organism, Current Opinion in Chemical Biology 12, 25-31. DOI: http://dx.doi.org/10.1016/j.cbpa.2008.02.011
- ^ Luheshi, L. M., Tartaglia, G. G., Brorsson, A.-C., Pawar, A. P., Watson, I. E., Chiti, F., Vendruscolo, M., Lomas, D. A., Dobson, C. M., and Crowther, D. C. (2007) Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity, PLoS Biol 5, e290.DOI: http://dx.doi.org/10.1371/journal.pbio.0050290
- ^ Crowther, D. C., Kinghorn, K. J., Miranda, E., Page, R., Curry, J. A., Duthie, F. A. I., Gubb, D. C., and Lomas, D. A. (2005) Intraneuronal AB, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease, Neuroscience 132, 123-135. DOI: http://dx.doi.org/10.1016/j.neuroscience.2004.12.025
- ^ Hammarström, P., Sekijima, Y., White, J. T., Wiseman, R. L., Lim, A., Costello, C. E., Altland, K., Garzuly, F., Budka, H., and Kelly, J. W. (2003) D18G Transthyretin Is Monomeric, Aggregation Prone, and Not Detectable in Plasma and Cerebrospinal Fluid: A Prescription for Central Nervous System Amyloidosis?, Biochemistry 42, 6656-6663. DOI: http://dx.doi.org/10.1021/bi027319b
- ^ Sekijima, Y., Wiseman, R. L., Matteson, J., Hammarström, P., Miller, S. R., Sawkar, A. R., Balch, W. E., and Kelly, J. W. (2008) The Biological and Chemical Basis for Tissue-Selective Amyloid Disease, Cell 121, 73-85. DOI: http://dx.doi.org/10.1016/j.cell.2005.01.018
- ^ Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R., and Morimoto, R. I. (2006) Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases, Science 311, 1471-1474. DOI: http://dx.doi.org/10.1126/science.1124514
- ^ Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W., and Dillin, A. (2006) Opposing Activities Protect Against Age-Onset Proteotoxicity, Science 313, 1604-1610. DOI: http://dx.doi.org/10.1126/science.1124646
- ^ Ramirez-Alvarado, M., Kelly, J. W., and Dobson, C. M., (Eds.) (2010) Protein Misfolding Diseases Current and Emerging Principles and Therapies, John Wiley and Sons, Hoboken