Polymorphism of ATTR amyloid fibrils from human tissue

• Applicant: Professor Dr. Marcus Fändrich
• Subject Area: Structural Biology ; Biochemistry
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447874287

• Final Report Year: 2024

Final Report Abstract

Systemic amyloid protein transthyretin (ATTR) amyloidosis is a rare but serious disease that arises from the formation of pathogenic aggregates and amyloid fibrils in different organs. ATTR amyloid fibrils result from misfolding of the blood protein transthyretin (TTR) or fragments thereof, whereby natively tetrameric TTR converts into an abnormal, pathogenic conformation. For the exact mechanistic understanding of this fundamental biochemical process and the possible design of specific ligands, it is essential to know the exact pathogenic structure. In this translational project, ATTR amyloid fibrils, containing wildtype (WT) or mutant TTR protein, were extracted from patient tissue, and their structures were analyzed by cryo-electron microscopy (cryo-EM). We found that all analyzed fibrils possess an essentially identical fold of the fibril proteins and an indistinguishable fibril morphology. The conclusions of this project are that there are common mechanistic steps in the misfolding of TTR protein in different patients and that the heterogenic symptoms of the different investigated ATTR patients do not arise from different fibril morphologies.

Publications

• Methods to study the structure of misfolded protein states in systemic amyloidosis. Biochemical Society Transactions, 49(2), 977-985.
  Fändrich, Marcus & Schmidt, Matthias
  
• Cryo-EM structure of an ATTRwt amyloid fibril from systemic non-hereditary transthyretin amyloidosis. Nature Communications, 13(1).
  Steinebrei, Maximilian; Gottwald, Juliane; Baur, Julian; Röcken, Christoph; Hegenbart, Ute; Schönland, Stefan & Schmidt, Matthias
  
• Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis. Nature Communications, 14(1).
  Steinebrei, Maximilian; Baur, Julian; Pradhan, Anaviggha; Kupfer, Niklas; Wiese, Sebastian; Hegenbart, Ute; Schönland, Stefan O.; Schmidt, Matthias & Fändrich, Marcus
  
• Cryo-EM structure and polymorphic maturation of a viral transduction enhancing amyloid fibril. Nature Communications, 14(1).
  Heerde, Thomas; Schütz, Desiree; Lin, Yu-Jie; Münch, Jan; Schmidt, Matthias & Fändrich, Marcus
  
• Cryo-EM Structure of the Full-length hnRNPA1 Amyloid Fibril. Journal of Molecular Biology, 435(18), 168211.
  Sharma, Kartikay; Banerjee, Sambhasan; Savran, Dilan; Rajes, Cedric; Wiese, Sebastian; Girdhar, Amandeep; Schwierz, Nadine; Lee, Christopher; Shorter, James; Schmidt, Matthias; Guo, Lin & Fändrich, Marcus
  
• Cryo-EM Analysis of the Effect of Seeding with Brain-derived Aβ Amyloid Fibrils. Journal of Molecular Biology, 436(4), 168422.
  Pfeiffer, Peter Benedikt; Ugrina, Marijana; Schwierz, Nadine; Sigurdson, Christina J.; Schmidt, Matthias & Fändrich, Marcus
  
• Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils. Nature Communications, 15(1).
  Sharma, Kartikay; Stockert, Fabian; Shenoy, Jayakrishna; Berbon, Mélanie; Abdul-Shukkoor, Muhammed Bilal; Habenstein, Birgit; Loquet, Antoine; Schmidt, Matthias & Fändrich, Marcus
  
• Insights into the Structural Basis of Amyloid Resistance Provided by Cryo-EM Structures of AApoAII Amyloid Fibrils. Journal of Molecular Biology, 436(4), 168441.
  Andreotti, Giada; Baur, Julian; Ugrina, Marijana; Pfeiffer, Peter Benedikt; Hartmann, Max; Wiese, Sebastian; Miyahara, Hiroki; Higuchi, Keiichi; Schwierz, Nadine; Schmidt, Matthias & Fändrich, Marcus