Amyloidosis affects millions of people, as a cause of Alzheimer's disease or a complication of dialysis, and also causes rare conditions. The many forms of the disorder have one underlying principle: misfolded proteins. Prompt, correct diagnosis is essential, especially in the inherited forms of amyloidosis. This article reviews the molecular basis of various types of amyloidosis and proposes new ways of treating these disorders.

Molecular mechanisms of amyloidosis.

Protein aggregation: folding aggregates, inclusion bodies and amyloid

Amyloidosis is not a single disease but a term for diseases that share a common feature: the extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues. In the mid-19th century, Virchow adopted the botanical term “amyloid,” meaning starch or cellulose, to describe abnormal extracellular material seen in the liver at autopsy.1 Subsequently, amyloid was found to stain with Congo red, appearing red microscopically in normal light but apple green when viewed in polarized light.2,3 Almost a century after Virchow's observations, the fibrillar nature of amyloid was described with the use of electron microscopy and the characteristic beta-pleated–sheet . . .

The Systemic Amyloidoses

Tissue deposition of soluble proteins as amyloid fibrils underlies a range of fatal diseases. The two naturally occurring human lysozyme variants are both amyloidogenic, and are shown here to be unstable. They aggregate to form amyloid fibrils with transformation of the mainly helical native fold, observed in crystal structures, to the amyloid fibril cross-beta fold. Biophysical studies suggest that partly folded intermediates are involved in fibrillogenesis, and this may be relevant to amyloidosis generally.

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Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis

Conformational constraints for amyloid fibrillation: the importance of being unfolded.

Light-chain (L-chain) amyloidosis is characterized by deposition of fibrillar aggregates composed of the N-terminal L-chain variable region (VL) domain of an immunoglobulin, generally in individuals overproducing a monoclonal L chain. In addition to proteolytic fragmentation and high protein concentration, particular amino acid substitutions may also contribute to the tendency of an L chain to aggregate in L-chain amyloidosis, although evidence in support of this has been limited and difficult to interpret. In this paper we identify particular amino acid replacements at specific positions in the VL domain that are occupied at frequencies significantly higher in those L chains associated with amyloidosis. Analysis of the structural model for the VL domain of the Bence-Jones protein REI suggests that these positions play important roles in maintaining domain structure and stability. Using an Escherichia coli expression system, we prepared single-point mutants of REI VL incorporating amyloid-associated amino acid replacements that are both rare and located at structurally important positions. These mutants support ordered aggregate formation in an in vitro L-chain fibril formation model in which wild-type REI VL remains soluble. Moreover, the ability of these sequences to aggregate in vitro correlates well with the extent to which domain stability is decreased in denaturant-induced unfolding. The results are consistent with a mechanism for the disease process in which the VL domain, either before or after proteolytic cleavage from the L-chain constant region domain, unfolds by virtue of one or more destabilizing amino acid replacements to generate an aggregation-prone nonnative state.

https://www.pnas.org/content/pnas/91/12/5446.full.pdf

Lin Li

Papers

A role for destabilizing amino acid replacements in light-chain amyloidosis