title: Small molecule oxidation products trigger disease-associated protein misfolding.
abstract: Oxidative stress and inflammation are risk factors for both the development of alpha-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, and Alzheimer's disease, the two most common neurodegenerative disorders. These diseases are associated with the neurotoxic deposition of misassembled alpha-synuclein and amyloid-beta (Abeta) peptides, respectively. Both occur sporadically, that is, without detectable disease-related mutations, in the vast majority of cases. Small molecule oxidation products, especially secosterols derived from cholesterol and 4-hydroxynonenal derived from lipid peroxidation, found in afflicted brains, accelerate the misassembly of both Abeta and alpha-synuclein. This Account explores the mechanism of small molecule oxidation product-mediated protein misassembly and possible intervention strategies.
authors.affiliation: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Bieschke
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Bosco
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Paul
authors.initials: P
authors.lastname: Wentworth
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D001704:Biopolymers; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015227:Lipid Peroxidation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017510:Protein Folding; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000682:Amyloid; D001704:Biopolymers; D051844:alpha-Synuclein; D002784:Cholesterol