EXAMINATION OF THE STRUCTURE OF THE TRANSTHYRETIN AMYLOID FIBRIL BY IMAGE-RECONSTRUCTION FROM ELECTRON-MICROGRAPHS

Familial amyloidotic polyneuropathies are autosomal-dominant, inherite d disorders that are characterised by the aggregation of variant prote ins in a fibrillar form and by the extracellular deposition of amyloid fibrils. In familial amyloidotic polyneuropathy type I the protein co nstituent is a variant transthyretin molecule that has a Val to Met su bstitution at residue 30. Patients with this form of the disease prese nt with sensory and motor disturbances, widespread autonomic dysfuncti on and in some cases, vitreous opacities. We have used amyloid materia l from the vitreous humours of patients homozygous for this mutation a nd analysed the structure of the fibrils by thin section electron micr oscopy and image reconstruction. Cross-sectional images of 200 differe nt fibrils were collected and aligned, manually at first and then with an automated process that uses iterative cross-correlation. The avera ged cross-section calculated produced a detailed view of the fibril su bstructure. The diameter of the fibrils is about 130 Angstrom. In cros s-section they exhibit 4-fold symmetry with four proto-filaments, each measuring 40 to 50 Angstrom across, arranged around a central hollow core. (C) 1995 Academic Press Limited