Cell toxicity and conformational disease.
Numerous disorders, including Alzheimer's, Parkinson's and other late-onset neurodegenerative diseases, arise from the conformationally driven aggregation of individual proteins. Previous focus on just one end-product of such aggregation - extracellular deposits of amyloid - has diverted attention from what is now recognized as being primarily intracellular disease processes. Recent structural findings show how cytotoxicity can result from even minor changes in conformation that do not lead to amyloid formation, as with the accumulation within the endoplasmic reticulum of intact mutant alpha-1-antitrypsin in hepatocytes and of neuroserpin in neurons. Studies in Alzheimer's and other dementias also indicate that the damage occurs at the stage of the initial intermolecular linkages that precede amyloid formation. The challenge now is to determine the detailed mechanisms of this cytotoxicity.
Carrell
Robin W
RW
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK CB2 2XY. rwc1000@cam.ac.uk
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D003704:Dementia / Q000209:etiology; D004194:Disease / Q000209:etiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004912:Erythrocytes / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010182:Pancreatic Diseases / Q000209:etiology / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D015843:Serpins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000097522:Neuroserpin
D000682:Amyloid; D009479:Neuropeptides; D011506:Proteins; D015843:Serpins; D000515:alpha 1-Antitrypsin; D000097522:Neuroserpin; C491937:Serpinb7 protein, rat