INVESTIGATION OF METABOLISM, FOLDING AND FIBRILLOGENESIS OF APOLIPOPROTEIN A1 VARIANTS CAUSING HEREDITARY AMYLOIDOSIS

Amyloidosis is a category of diseases caused by 20 different proteins that in particular conditions can lose their tertiary interactions and self aggregate into cytotoxic fibrils. The type of protein, the involved tissue and the timing of cellular toxicity create various diseases such as Alzheimer's disease, spongiform encephalopathy and several hereditary amyloidoses. Our project is focused on the mechanism of amyloid formation caused by variants of apolipoprotein A1(apoA1): the lipoprotein that normally remove the excess of cholesterol. Our group (http://www.amiloidosi.it/) has shown that apoA1 variants are responsible for two types of hereditary amyloidosis in Italy (Obici et al 1999-Mangione et al 2001). In these cases we have made two original discoveries: 1) The pathogenic part of the protein corresponds to 93 N-terminal residues. 2) In the high density lipoproteins of our heterozygous patients (who have 50% normal DNA and 50% mutated DNA) 75% of the apoA1 is normal and 25% is mutated. We, therefore, have two aims: 1) elucidation of the conditions that cause the release of the toxic part of the protein (the N-terminus of the 93 residues) and elucidation of the mechanism of fibril formation; 2) understanding of the biochemical basis of the excess of normal protein in HDL. The two targets of the research have therapeutic implications: 1) the way which the 93 residue N-terminal domain is released could represent a therapeutic target (i.e. the use of anti-proteases). The unbalanced level of circulating wild type apoA1 suggests that two possible mechanisms are involved: faster degradation and/or faster deposition into amyloid fibrils. We believe that the two phenomena might possibly coexist and that understanding their mechanisms would help in designing therapies aimed at increasing the degradation rather than the formation of fibrils.