baudrunner's space: Misfolded proteins, evolution, and coffee
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Monday, January 21, 2008

Misfolded proteins, evolution, and coffee

In a previous post I discussed the nature of the disease we know as Alzheimer's. The culprit of this tragic affliction is the prematurely cleaved linear amino acid peptide, the beta amyloid precursor protein whose mutated form has become known as the prion (pronounced prē'ŏn). The process which gives these peptides their mutant characteristic was discovered by the late great Vernon Ingram. His studies on the action upon the precursor protein within the hydrophobic layer of the cell wall should not be dismissed. It has been estimated that 30-40% of encoded DNA codes for membrane proteins, thereby offering a large probability of divergence from normal translation to those proteins.

The prions that give rise to the development of Alzheimer's disease have been included in the class of misfolded proteins which contribute to some twenty known disorders related to the accumulation of beta amyloid fibrils or plaques in organs such as the brain, liver or spleen. These include Type II Diabetes and Huntington's disease. It is no mystery then that sufferers of diabetes have a 65 per cent higher risk of developing Alzheimer’s disease, according to a study published in the Archives of Neurology. Alzheimer's is estimated to be the most expensive medical problem in the Western world.

Recent advances in the understanding of the nature of protein misfolding has revealed that this trait is a generic property of polypeptide chains and that this indicates that

"..a key feature of biological evolution has been the selection of protein sequences with inherent resistance to aggregation, coupled with mechanisms that normally ensure effective control and regulation of misfolding and aggregation in the cell."
The above extract was taken from a paper by Christopher M. Dobson of the University of Cambridge, Department of Chemistry. He describes the associated diseases as "becoming increasingly prevalent in the modern world". What are also becoming increasingly prevalent in the modern world are the advanced technologies that are used to make these discoveries. For example, data from highly advanced mass spectrometers are now being used to characterize particular protein components from the spectra of intact ribosomes (RNAs are transcribed from DNA and the RNAs are translated into proteins by ribosomes).

A protein is synthesized from the information represented by the base sequences of the particular RNA molecule which determine which amino acid is next in the assembly process. The final product is the protein, which normally folds into the three-dimensional shape as determined by their molecular arrangement. Competition in the intracellular environment determines the effectiveness of this process. The protein may misfold or degrade. It has been observed for example that the crowding effect of high concentrations of macromolecules in the cytoplasm of the cell can have a detrimental effect. Some of these macromolecules are actually represented by any of at least twenty different families of molecular "chaperones", which facilitate the at times complex folding process. Others are enzymes which catalyze some of the slower processes involved in folding. Evolution is an ongoing process. The research team at the Oxford Centre for Molecular Sciences has observed that one of the roles of molecular chaperones is to prevent the aggregation of partially folded proteins.

At least four different approaches to possible therapies which address the root causes of the prion diseases and the possible eradication of the misfolded proteins are being examined based on the knowledge derived from ongoing research. These were described at a workshop held at St Catherine's College, Oxford, from March 25–28, 1998, attracting participants from 32 nations. Some of the information contained above is culled from a report produced by Christopher M. Dobson and R. John Ellis, of the Oxford Centre for Molecular Sciences.

In a more recent development (updated: October 6, 2006), at the risk of stepping into controversial territory it should be noted that U.S. FDA approved medications currently available for treating Alzheimer's disease do not appear as effective in inhibiting formation of amyloid plaque as does Tetrahydrocannabinol or THC, the active component found in Marijuana. This was discovered by researchers at the Scripps Research Institute.

And research on mice conducted at the Byrd Alzheimer's Institute in Florida has revealed that coffee may have a beneficial effect on patients with Alzheimer's. Regular intake of caffeinated water by mice with prions in their brain cells showed reduced numbers of those prions compared to a control group, and memory studies on Alzheimer mice after ingestion of caffeinated water showed results equal to a control group.

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