Common mechanisms of amyloid oligomer pathogenesis in degenerative disease.
Many age-related degenerative diseases, including Alzheimer's, Parkinson's, Huntington's diseases and type II diabetes, are associated with the accumulation of amyloid fibrils. The protein components of these amyloids vary widely and the mechanisms of pathogenesis remain an important subject of competing hypotheses and debate. Many different mechanisms have been postulated as significant causal events in pathogenesis, so understanding which events are primary and their causal relationships is critical for the development of more effective therapeutic agents that target the underlying disease mechanisms. Recent evidence indicates that amyloids share common structural properties that are largely determined by their generic polymer properties and that soluble amyloid oligomers may represent the primary pathogenic structure, rather than the mature amyloid fibrils. Since protein function is determined by the three-dimensional structure, the fact that amyloids share generic structures implies that they may also share a common pathological function. Amyloid oligomers from several different proteins share the ability to permeabilize cellular membranes and lipid bilayers, indicating that this may represent the primary toxic mechanism of amyloid pathogenesis. This suggests that membrane permeabilization may initiate a core sequence of common pathological events leading to cell dysfunction and death that is shared among degenerative diseases, whereas pathological events that are unique to one particular type of amyloid or disease may lie in up stream pathways leading to protein mis-folding. Although, these upstream events may be unique to a particular disease related protein, their effects can be rationalized as having a primary effect of increasing the amount of mis-folded, potentially amyloidogenic proteins.
Glabe
Charles G
CG
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA. cglabe@uci.edu
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D046911:Macromolecular Substances; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship
D000682:Amyloid; D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances