Small molecule oxidation products trigger disease-associated protein misfolding.
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.
Bieschke
Jan
J
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Zhang
Qinghai
Q
Bosco
Daryl A
DA
Lerner
Richard A
RA
Powers
Evan T
ET
Wentworth
Paul
P
Kelly
Jeffery W
JW
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
D000447:Aldehydes; D000682:Amyloid; D001704:Biopolymers; D051844:alpha-Synuclein; D002784:Cholesterol