Polymorphism of ATTR amyloid fibrils from human tissue

• Applicant: Professor Dr. Marcus Fändrich
• Subject Area: Structural Biology ; Biochemistry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447874287

Systemic ATTR amyloidosis is a rare but serious disease that relies on the formation of pathogenic aggregates and amyloid fibrils in different organs. ATTR amyloid fibrils result from misfolding of the blood protein transthyretin or fragments thereof, with transthyretin assuming not its native tetrameric structure but an abnormal, pathogenic conformation. For the exact mechanistic understanding of this fundamental biochemical process and the possible design of specific ligands, the exact understanding of the pathogenic structure is essential. In this translational project, ATTR amyloid fibrils are extracted from patient tissue and their structure analyzed by cryo-electron microscopy. Cryo-electron microscopy is uniquely suited for the study of protein structures in biopsy material as it does not require isotope labels or crystals. In particular, the project aims to decipher the molecular basis of the development of various disease variants of ATTR amyloidosis and thus to create conditions for a better understanding of the pathogenic misfolding mechanism.

• DFG Programme: Research Grants