CURRENT CONCEPTS ON THE PATHOGENESIS OF SYSTEMIC AMYLOIDOSIS

Amyloidosis is a pathological condition in which protein is deposited extracellularly in the form of insoluble fibrils that lead to organ dy sfunction and death. Many different types of proteins are known to for m amyloid and cause a heterogeneous array of clinical conditions. The unifying aspect of these conditions is the common structural entity re sulting from the assembly of a primarily beta-structure protein into 5 -10 nm wide non-branching insoluble fibrils displaying the characteris tic green birefringence of bound Congo red dye when viewed under polar ized light. Several factors contribute to amyloid assembly. Certain bi ophysical characteristics of the amyloidogenic precursor influence amy loidogenicity. Any mutation that sufficiently decreases protein stabil ity favours the formation of a partially folded state under physiologi cal conditions. This intermediate exposes other key sequence elements to the solvent, i.e. hydrophobic or charged residues that decrease sol ubility and promote aggregation and ultimately amyloid formation. In a ddition to primary protein structure, which confers a susceptibility t o amyloid formation, other elements are probably important for the ini tiation, development and persistence of amyloid deposits: proteoglycan s, 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 beta-2-microglobulin amyloidosis. A detailed understanding of the molecular processes lead ing to amyloid deposition is required for the development of effective therapies.