Current concepts on the pathogenesis of systemic amyloidosis

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Abstract
Amyloidosis is a pathological condition in which protein is deposited extracellularly in the form of insoluble fibrils that lead to organ dysfunction and death. Many different types of proteins are known to form amyloid and cause a heterogeneous array of clinical conditions. The unifying aspect of these conditions is the common structural entity resulting from the assembly of a primarily β-structure protein into 5–10 nm wide non-branching insoluble fibrils displaying the characteristic green birefringence of bound Congo red dye when viewed under polarized light. Several factors contribute to amyloid assembly. Certain biophysical characteristics of the amyloidogenic precursor influence amyloidogenicity. Any mutation that sufficiently decreases protein stability favours the formation of a partially folded state under physiological conditions. This intermediate exposes other key sequence elements to the solvent, i.e. hydrophobic or charged residues that decrease solubility and promote aggregation and ultimately amyloid formation. In addition to primary protein structure, which confers a susceptibility to amyloid formation, other elements are probably important for the initiation, development and persistence of amyloid deposits: proteoglycans, amyloid P component, apolipoprotein E and others, most of which are normal constituents of basement membranes. The role of these factors in amyloidogenesis has been studied in two major systemic amyloidoses with prominent renal involvement: light-chain and β-2-microglobulin amyloidosis. A detailed understanding of the molecular processes leading to amyloid deposition is required for the development of effective therapies.

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