A spectroscopic study of some of the peptidyl radicals formed following hydroxyl radical attack on beta-amyloid and alpha-synuclein.
There is clear evidence implicating oxidative stress in the pathology of many neurodegenerative diseases. Reactive oxygen species (ROS) are the primary mediators of oxidative stress, and hydrogen peroxide, a key ROS, is generated during aggregation of the amyloid proteins associated with some of these diseases. Hydrogen peroxide is catalytically converted to the aggressive hydroxyl radical in the presence of Fe(II) and Cu(I), which renders amyloidogenic proteins such as beta-amyloid and alpha-synuclein (implicated in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively) vulnerable to self-inflicted hydroxyl radical attack. Here, we report some of the peptide-derived radicals, detected by electron spin resonance spectroscopy employing sodium 3,5-dibromo-4-nitrosobenzenesulfonate as a spin-trap, following hydroxyl radical attack on Abeta(1-40), alpha-synuclein and some other related peptides. Significantly, we found that sufficient hydrogen peroxide was self-generated during the early stages of aggregation of Abeta(1-40) to produce detectable peptidyl radicals, on addition of Fe(II). Our results support the hypothesis that oxidative damage to Abeta (and surrounding molecules) in the brain in AD could be due, at least in part, to the self-generation of ROS. A similar mechanism could operate in PD and some other "protein conformational" disorders.
Tabner
Brian J
BJ
Magnetic Resonance Laboratory, Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, UK.
Turnbull
Stuart
S
King
Jenny E
JE
Benson
Fiona E
FE
El-Agnaf
Omar M A
OM
Allsop
David
D
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001557:Benzenesulfonates / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D009603:Nitroso Compounds / Q000737:chemistry; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D001557:Benzenesulfonates; D005296:Ferrous Compounds; D009603:Nitroso Compounds; D010446:Peptide Fragments; D010455:Peptides; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D017665:Hydroxyl Radical; C048757:3,5-dibromo-4-nitrosobenzenesulfonate