FOR 2969:  Mechanisms of antibody light chain misfolding in systemic AL amyloidosis

• Subject Area: Biology
• Term: from 2019 to 2023
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410477202

The light chain or AL amyloidosis is one of the most abundant types of systemic amyloidosis in Germany. Advanced kidney or heart involvement can lead to rapid dialysis or death. The disease is caused by the misfolding and aggregation of antibody light chains, which are produced in the course of a monoclonal B-call disorder. A particular remarkable feature of AL amyloidosis is thevariability of its clinical manifestations. This heterogeneity is probably caused by the natural diversity of light chains and of the polymorphic aggregate structure. However, the exact relationships are not so far understood. This research unit aims to clarify for two specifically prominent clinical forms of AL amyloidosis (dominant heart or kidney involvement) how disease and clinical manifestations arise from protein biochemical properties. We will investigate in particular the primary structure, the proteolytic processing, the folding and the polymorphic aggregate structure. A broad methodological spectrum supports our research strategy which primarily seeks to improve the basic understanding but which may also create direct benefit for patients, for example in the early diagnosis.

• DFG Programme: Research Units

Projects

• Analysis of the pathological effects of light chains and AL protein states (Applicants Amann, Kerstin ;  Röcken, Christoph )
• Conformational dynamics and misfolding of the fibril precursor proteins studied by NMR (Applicant Reif, Bernd )
• Coordination Funds (Applicant Fändrich, Marcus )
• Cryo-EM structures of AL amyloid fibrils from human heart (Applicant Fändrich, Marcus )
• Dissection of the molecular fibril formation pathway of patient-derived light chain variants (Applicant Buchner, Johannes )
• Sequence diversity of the light chains in two clinical variants of AL amyloidosis (Applicants Huhn, Stefanie ;  Schönland, Stefan )
• Variation of the AL protein primary structure in two clinical variants of AL amyloidosis (Applicants Haupt, Christian ;  Hegenbart, Ute )

• Spokesperson: Professor Dr. Marcus Fändrich