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Systemic AL amyloidosis is a rare disease that originates from an abnormally proliferating plasma cell producing an excess of a patient-specific light chain. These free light chains are secreted into the blood and deposit as amyloid fibrils in different organs leading to diverse pathology. Studies have shown that primary structural elements destabilize the light chains or create aggregation-prone regions that eventually lead to fibril formation. Furthermore, it is discussed whether light chain truncation could influence fibril formation. However, until today it is unknown whether proteolysis of the light chains occurs before or after fibril formation and if fragmentation affects amyloidogenicity. In addition, most information on the primary structure of LCs and AL proteins is derived from cDNA sequences, which are often incomplete and lack information about truncation sites and other PTMs of the AL proteins. Thus, it is still largely unknown which concrete properties and mutations increase the amyloidogenicity of LCs. This study addresses the question of the timing of LC proteolysis by analyzing the body fluids of AL amyloidosis patients for LCs and their fragments. This study also presents a new mass spectrometry-based method to determine the primary structure of AL proteins using protein information. Applying this method resulted in the identification of the primary structure of the AL proteins in 19 cases. Comparing the AL proteins revealed commonalities in post-translational modifications, truncation sites, and mutations. |
