Amyloid aggregate formation

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

The model of amyloid fibril formation is a nucleation step followed by growth, where the nucleation mechanism dictates the concentration and time dependence of the aggregation (Harper and Lansbury, 1997 ... 

Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T., and Lansbury, P. T., Jr. (2002). Alpha-synuclein, especially the Parkinson s disease-associated mutants, forms pore-like annular and tubular protofibrils./. Mol. Biol. 322,1089-1102. LeVine, H. (1993). Thioflavine T interaction with synthetic Alzheimer s disease beta-amyloid peptides Detection of amyloid aggregation in solution. Protein Sci. 2, 404—410. Lin, H., Bhatia, R., and Lai, R. (2001). Amyloid beta protein forms ion channels Implications for Alzheimer s disease pathophysiology. FASEB J. 15, 2433-2444. Lorenzo, A., and Yankner, B. A. (1994). Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc. Natl. Acad. Sci. USA 91, 12243-12247. Luhrs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Dobeli, H., Schubert, D., and Riek, R. (2005). 3D structure of Alzheimer s amyl o id-( be la) (1—12) fibrils. Proc. Natl. Acad. Sci. USA 102, 17342-17347. 

The extreme stability of amyloid and amyloid-like fibrils is difficult to understand in terms of the three classes of fibril models. For the Refolding models, it has been suggested that the amyloid conformation is a default conformation for a polypeptide chain (Dobson, 1999). However, these models do not give a clear indication of what types of interactions differ in the amyloid conformation versus the native conformation, and so it is unclear why the amyloid conformation should be more stable. Also, it seems that the elevated protein concentrations associated with fibril formation might disproportionately favor nonspecific aggregation of the destabilized intermediate over amyloid fibril formation. 

As discussed earlier, conformational change/structural perturbation is a prerequisite for amyloid formation. Exposure to UV light did not initiate the fibril formation it led to amorphous aggregation of prion protein and no observable change to the other two proteins. We have employed conditions that are known to favor amyloid fibril formation and investigated the effect of UV light exposure of these proteins on their ability to form amyloid fibrils. 

Kim YS, Randolph TW, Manning MC, Stevens FJ, Carpenter JF. Congo Red populates partially unfolded states of an amyloidogenic protein to enhance aggregation and amyloid fibril formation. J. Biol. Chem. 2003 278 10842-10850. 

Tanshinones. Tanshinones extracted from Chinese herb Danshen Salvia Miltiorrhiza Bunge) were traditionally used as antiinflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. Tanshinones protect neuronal cells. Tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, inhibit the aggregation and toxicity of Ap1 42 Both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2 [235]. 

Crocin is a carotenoid from the stigma of the saffron flower with many medicinal properties, including antioxidant effects. Crocin has the ability to prevent amyloid formation. The antiamy-loidogenic effect of crocin may be exerted not only by the inhibition of Ap amyloid formation but also by the disruption of amyloid aggregate [384],... 

Two basic models have been proposed for amyloid fibril formation from the intermediates.In the nucleation model, the intermediates cluster to form nuclei. Fibril is formed from the nucleus after the nucleus has reached a critical size. Such fibrils add on to its ends to form aggregates. In the polymerization model, intermediate peptide-PF complexes are formed and associate end to end or laterally to form fibrils. 

The structure of transthyretin. The molecule contains eight antiparallel A-strands (A-H) arranged in two parallel planes. The circulating form of transthyretin is a tetramer. Some mutations in the transthyretin gene are associated with amyloidosis and eight of the amino acid alterations causing this disease are indicated. In plasma, transthyretin is a tetramer composed of identical monomers. It appears that mutations cause the monomeric unfolded intermediate of transthyretin to aggregate into an insoluble A-amyloid fibril formation. 

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