Amyloidogenic proteins, diseases

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... 

He P, Li P, Hua Q, Liu Y, Staufenbiel M, Li R et al (2013) Chronic administration of antistroke herbal medicine TongLuoJiuNao reduces amyloidogenic processing of amyloid precursor protein in a mouse model of Alzheimer s disease. PLoS One 8 e58181. doi 10.1371/journal.pone.0058181... 

Table 1 Pathological amyloid proteins and their precursors, associated diseases and amyloidogenic sequences... 

In contrast, the two other amyloid diseases associated with TTR, familial amyloidotic polymeuropathy-l (FAP-1) and familial amyloidotic cardiomyopathy (FAC), are both autosomal dominant disorders (Table 1). The deposits of amyloid fibrils in these disorders form in tissues and organs and are made up of variant TTR, wt protein and TTR fragments. More than 80 TTR variants have been reported, with the majority of these being associated with disease (Hamilton and Benson 2001). These are single amino acid substitutions, with the exception of a Vall22 deletion mutation. It appears that certain amino acid substitutions decrease the stability of the tetramer and favour the formation of amyloidogenic intermediates that can then self-associate to form fibrils. FAR is usually fatal within 7 to 15 years after the appearance of symptoms. 

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