The lipid peroxidation metabolite 4-oxo-2-nonenal cross-links alpha-synuclein causing rapid formation of stable oligomers.
Recently, the aldehyde 4-oxo-2-nonenal (ONE) was identified as a product of lipid peroxidation and found to be an effective protein modifier. In this in vitro study we investigated structural implications of the interaction between ONE and alpha-synuclein, a protein which forms intraneuronal inclusions in neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. Our results demonstrate that ONE induced an almost complete conversion of monomeric alpha-synuclein into 40-80 nm wide and 6-8 nm high soluble beta-sheet-rich oligomers with a molecular weight of approximately 2000 kDa. Furthermore, the ONE-induced alpha-synuclein oligomers displayed a high stability and were not sensitive to treatment with sodium dodecyl sulfate, indicating that ONE stabilized the oligomers by cross-linking individual alpha-synuclein molecules. Despite prolonged incubation the oligomers did not continue to aggregate into a fibrillar state, thus suggesting that these alpha-synuclein species were not on a fibrillogenic pathway.
Näsström
Tomas
T
Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Wahlberg
Therese
T
Karlsson
Mikael
M
Nikolajeff
Fredrik
F
Lannfelt
Lars
L
Ingelsson
Martin
M
Bergström
Joakim
J
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D015227:Lipid Peroxidation; D018625:Microscopy, Atomic Force; D008970:Molecular Weight; D020734:Parkinsonian Disorders / Q000378:metabolism; D011487:Protein Conformation; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
C403894:4-oxo-2-nonenal; D000447:Aldehydes; D000682:Amyloid; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate