Creation of "Amyloid" Fibrils from Bence Jones Proteins in vitro

Abstract

"Amyloid" fibrils have been created from some human Bence Jones proteins by proteolytic digestion under physiologic conditions. These fibrils with an antiparallel, beta-pleated sheet conformation consist of only a portion of the variable region of the immunoglobulin light polypeptide chain and share the physical properties of amyloid fibrils. The relation between amyloidosis and immunoglobulins is thus more firmly established and a pathogenetic mechanism for amyloid fibril formation is suggested.

The protein component of scrapie-associated fibrils is a glycosylated low molecular weight protein.

“…However, it should be stressed again that all these proteins, i.e., amyloid core proteins in Alzheimer's disease and aged Down's syndrome and the SAF-polypeptide from scrapie hamster brains, are small polypeptides of 4 kd and 7 kd, respectively. This size is shared with 'amyloid' fibrils created in vitro from Bence-Jones proteins (Glenner et al, 1971) and other amyloid-fibril proteins (Glenner, 1980;Glenner and Wong, 1984;Masters et al, 1985). The inability of these small proteins to form fl-barrel structures, i.e., closed-end f-pleated sheets requiring six f-strands and at least 100 residues, may lead to an uncontrolled polymerization resulting in the various forms of amyloids.…”

The partial amino acid sequence of the major low molecular weight component of two human amyloid fibrils

“…Thus it seems likely that it may constitute a major component of amyloid substance of diverse origin [2,6,7] . This component seems to be present in addition to the immunoglubulin fragments demonstrated by Glenner et al [8] since examination of the peptide map of one of these proteins (FMF) indicates the presence of peptides characteristic of the acid soluble fraction as well as those which appear to be com- References Whether this protein is synthesized and deposited as such, or represents a fragment of a larger protein remains to be determined. The heterogeneity and presence of arginine at the amino terminus raise the possibility that it is the product of proteolytic digestion of a larger protein.…”

A novel replicating agent isolated from the human intestinal tract having characteristics shared with Creutzfeldt-Jakob and related agents

“…This notion is prompted by analogy with amyloid with which IFDO (and slow viruses) share the property of birefringence as well as resistance to digestion by proteolytic enzymes. Formation of amyloid in uitro has been demonstrated with certain Bence-Jones proteins in the presence of pepsin (Glenner et al, 1971), and with intact p 2-microglobulin without enzyme pretreatment (Connors et al, 1985). The crystallisation hypothesis might explain the low level of observed contamination if initial growth of IFDO is the result of a rare spontaneous event.…”