Special LMNN Seminar - Polymorphism of amyloid fibrils revealed by cryo electron microscopy

Polymorphism describes the structural variations of amyloid fibrils formed by a given polypeptide chain. While there has been long-standing evidence that structural variations of fibrils could underlie different disease variants, it remained controversial as to whether or not the fibrils within one patient or diseased animal are isomorphic. Using improved methods to purify amyloid fibrils from diseased tissue and electron microscopy we found that polymorphism is a conserved structural feature of all analysed amyloid fibrils in vivo. That is, irrespective of whether we analysed diseased animals or patients, amyloid deposits in different organs, different amyloid precursor proteins and different forms of amyloid diseases we uniformly found amyloid fibril polymorphism in one organism. Furthermore, the same structural variations could be seen when analysing filaments from different tissues of the same patient. To obtain insights into the molecular basis of amyloid fibril polymorphism, we used cryo electron microscopy and applied it to fibrils formed from a peptide fragment of an immunoglobulin light chain underlying systemic AL amyloidosis. We find that the structure of experimentally observable fibril topologies can be rationalized and predicted based on a small number of physical parameters. Our data imply that a competition of molecular forces arising from β-sheet twist and cross-sectional interactions determines the formation of the specific fibril architectures and their polymorphism in the experimental sample.