Mutational studies, protein aggregation

A great deal of information is available on the role of point mutations, abnormal proteins (A/ , presenilin, phospharylated aggregated tau) and various environmental factors [aluminum (Al), head injury, etc.] involved in AD neurodegeneration [24]. Limited headway was made in the therapeutic aspects of AD because of the complexity of the disorder. There are few studies concerning modulations... 

CD spectroscopy has also provided valuable insight into the chemical stability and chemical denaturation of proteins. A recent study by Rumfeldt etal. examines the guanidinium-chloride induced denaturation of mutant copper-zinc superoxide dismutases (SODs). These mutant forms of the Cu, Zn-SOD enzyme are associated with toxic protein aggregation responsible for the pathology of amyotrophic lateral sclerosis. In this study, CD spectroscopy was used in conjunction with tryptophan fluorescence, enzyme activity, and sedimentation experiments to study the mechanism by which the mutated enzyme undergoes chemical denaturation. The authors found that the mutations in the enzyme structure increased the susceptibihty of the enzyme to form partially unfolded destabilized monomers, rather than the stable metaUated monomer intermediate or native metallated dimer. 

The propensities of folded proteins to aggregate will therefore depend on the accessibility of such aggregation-prone species, a conclusion that is clearly demonstrated by detailed studies of the amyloidogenic mutational variants of lysozyme, which we have found to decrease the stability and cooperativity of the native state (Fig. 13.4) [40-43]. Indeed, these experiments show that the effect of the disease-associated mutations is to decrease the energy difference between the native state and the intermediates populated in the normal folding of the protein, such that the latter are accessible to a much greater extent in the variants than in the wild-type protein [40]. The large mass of evidence now accumulated from studies of lysozyme has provided detailed... 

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