Amyloidosis Amyloid fibrils

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. 

Unfortunately, the description of amyloid fibrils given above is simplistic since in vitro self-assembly of amyloid peptides and proteins yields polymorphic structures, as has been commonly observed in the past for other protein assemblies such as actin filaments (Millonig et al, 1988) and intermediate filaments (Herrmann and Aebi, 1999). On the one hand, assembly polymorphism complicates the characterization of fibril structure. On the other hand, it offers some insight into fibril formation. For this reason a more rational understanding of amyloid fibril formation at the molecular level is a key issue in the field of amyloidosis. 

A prime example of a Refolding model is that of the insulin protofilament (Jimenez et al., 2002). Insulin is a polypeptide hormone composed of two peptide chains of mainly o -helical secondary structure (Fig. 3A Adams et al., 1969). Its chains (21- and 30-amino acids long) are held together by 3 disulfide bonds, 2 interchain and 1 intrachain (Sanger, 1959). These bonds remain intact in the insulin amyloid fibrils of patients with injection amyloidosis (Dische et al., 1988). Fourier transform infrared (FTIR) and circular dichroic (CD) spectroscopy indicate that a conversion to jS-structure accompanies insulin fibril formation (Bouchard et al., 2000). The fibrils also give a cross-jS diffraction pattern (Burke and Rougvie, 1972). 

C9. Cohen, D. H., Feiner, H., Jensson, O., and Frangione, B., Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace. J. Exp. Med. 158(2), 623-628 (1983). 

G2. Ghiso, J., lensson, O., and Frangione, B., Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of y -trace basic protein (cystatin C). Proc. Natl. Acad. Set (USA) 83(9), 2974-2978 (1986). 

Cohen AS. General introduction and a brief history of the amyloid fibril. In Amyloidosis. Marrick J, Van Rijswijk MH, eds. 1986. Nijhoff, Dordrecht, The Netherlands, pp. 3-19. 

Brus I, Steiner G, Maceda A, Lejano R. Amyloid fibrils In urinary sediment. Fleroln addiction with renal amyloidosis. NY State J Med 1979 79 768-771. 

Most TTR variants are associated with extracellular deposition of amyloid fibrils in various tissue. These autosomal dominant hereditary amyloidoses include amyloidotic cardiomyopathy, familial amyloidotic polyneuropathy, and senile systemic amyloidosis. There is phenotypic variability (e.g., variable age of onset), suggesting that other factors may influence pathogenesis of the diseases. 

The formation of this insoluble variety of protein, resistant to normal proteolysis due to its P-conformation, is the one characteristic common to aU types of amyloid, whatever their composition. Amyloid fibrils may have multiple soluble plasma protein precursors that are either increased in quantity or modified by proteolysis to make them insoluble. The result is a disease group with diverse etiologies, called amyloidosis. The deposits can be local or systemic. They exert pressure on vital structures and eventually cause death. No details are known about the local mechanism of formation of these deposits or the determinant for the site of deposition. 

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. 

The clinician can determine whether a patient such as Katta Bolic is j mounting an acute phase response to some insult, however subtle, by deter- mining whether several unique acute phase proteins are being secreted by the liver. C-reactive protein, so named because of its ability to interact with the C-polysaccharide of pneumococci, and serum amyloid A protein, a precursor of the amyloid fibril found in secondary amyloidosis, are elevated in patients undergoing the acute phase response and as compared with healthy individuals. Other proteins normally found in the blood of healthy individuals are present in increased concentrations in patients undergoing an acute phase response. These include haptoglobin, certain protease inhibitors, complement components, ceruloplasmin, and fibrinogen. The elevated concentration of these proteins in the blood increases the erythrocyte sedimentation rate (ESR), another laboratory measure of the presence of an acute phase response. 

An instractive example of the effect of cysteine modification on amyloid formation is provided by the TTR protein. This plasma protein is a tetramer in solution, with four identical 127 amino acid sub-units and is responsible for transport of thyroxine and the retinol-binding protein-vitamin A complex (Hamilton and Benson 2001). Deposition of wtTTR occurs in senile systemic amyloidosis (SSA) (Table 1). This is a non-hereditary disorder that affects roughly 25% of individuals over the age of 80. The amyloid fibrils formed consist mainly of wfTTR and its fragments, and they build up in the heart. 

Isobe T, Osserman EF (1974) Patterns of amyloidosis and their association with plasma cell dyscrasias, monoclonal immunc lobulins and Bence Jones proteins. N Engl J Med 290 473-477 Ivanova Ml, Gingery M, Whitson LJ, Eisenba-g D (2003) Role of the C-terminal 28 residues of beta 2-microglobulin in amyloid fibril formation. Biochemistry 42 13536-13540 Iwata K, Fujiwara T, Matsuki Y, Akutsu H, Takahashi S, Naiki H, Goto Y (2006) 3D structure of amyloid protofilaments of beta 2-micrc lobulin fragment probed by solid-state NMR. Proc Natl Acad Sci USA 103 18119-18124... 

---