Role of C-terminal truncations of SAA protein for fibril formation and seeding in AA amyloidosis

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Systemic AA amyloidosis is a conformational disease that affects both animals and humans and that is caused by AA amyloid fibrils. These filaments consist of N-terminal fragments of serum amyloid A (SAA) protein, but different clinical variants of the disease are associated with different SAA protein fragments. These data suggest an involvement of different fibril strains in different disease manifestations. To test these ideas, I will here probe the relationship between C-terminal truncation, proteolysis and fibril formation, and dissect out the structural effects of C-terminal truncation on protein structure and fibrillogenesis. Obtained results will then be used to explore whether or how seeding might vary in efficiency with fibril structure or sequence complementarity (species barrier) and whether certain fibril morphologies are able to propagate structural specifics or phenotypic manifestations in a strain-type fashion. Proposed experiments range from protein biochemical techniques and biophysics to cell biological and animal studies in mice. Expected results data will provide vital information for understanding the nature and molecular etiology of AA amyloidosis and the effectiveness of common molecular mechanisms in different types of conformational diseases.