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.
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Hilal A
HA
Lashuel
Dean
D
Hartley
Benjamin M
BM
Petre
Thomas
T
Walz
Peter T
PT
Lansbury
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