Prefibrillar amyloid aggregates could be generic toxins in higher organisms.
More than 40 human diseases are associated with fibrillar deposits of specific peptides or proteins in tissue. Amyloid fibrils, or their precursors, can be highly toxic to cells, suggesting their key role in disease pathogenesis. Proteins not associated with any disease are able to form oligomers and amyloid assemblies in vitro displaying structures and cytotoxicity comparable with those of aggregates of disease-related polypeptides. In isolated cells, such toxicity has been shown to result from increased membrane permeability with disruption of ion homeostasis and oxidative stress. Here we microinjected into the nucleus basalis magnocellularis of rat brains aggregates of an Src homology 3 domain and the N-terminal domain of the prokaryotic HypF, neither of which is associated with amyloid disease. Prefibrillar aggregates of both proteins, but not their mature fibrils or soluble monomers, impaired cholinergic neuron viability in a dose-dependent manner similar to that seen in cell cultures. Contrary to the situation with cultured cells, however, under our experimental conditions, cell stress in tissue is not followed by a comparable level of cell death, a result that is very likely to reflect the presence of protective mechanisms reducing aggregate toxicity. These findings support the hypothesis that neurodegenerative disorders result primarily from a generic cell dysfunction caused by early misfolded species in the aggregation process.
Baglioni
Serena
S
Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy.
Casamenti
Fiorella
F
Bucciantini
Monica
M
Luheshi
Leila M
LM
Taddei
Niccolò
N
Chiti
Fabrizio
F
Dobson
Christopher M
CM
Stefani
Massimo
M
D000682:Amyloid / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D019878:Carboxyl and Carbamoyl Transferases; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins; D008297:Male; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D011506:Proteins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014118:Toxins, Biological / Q000633:toxicity
D000682:Amyloid; D029968:Escherichia coli Proteins; D011506:Proteins; D014118:Toxins, Biological; D019878:Carboxyl and Carbamoyl Transferases; C504838:hypF protein, E coli