Neurodegenerative disease: amyloid pores from pathogenic mutations.
Alzheimer's and Parkinson's diseases are associated with the formation in the brain of amyloid fibrils from beta-amyloid and alpha-synuclein proteins, respectively. It is likely that oligomeric fibrillization intermediates (protofibrils), rather than the fibrils themselves, are pathogenic, but the mechanism by which they cause neuronal death remains a mystery. We show here that mutant amyloid proteins associated with familial Alzheimer's and Parkinson's diseases form morphologically indistinguishable annular protofibrils that resemble a class of pore-forming bacterial toxins, suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases.
Lashuel
Hilal A
HA
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Hartley
Dean
D
Petre
Benjamin M
BM
Walz
Thomas
T
Lansbury
Peter T
PT
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D002463:Cell Membrane Permeability / Q000187:drug effects; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006801:Humans; D008954:Models, Biological; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018272:Porins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051843:Synucleins; D051844:alpha-Synuclein
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D018272:Porins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein