Journal
BIOCHEMICAL JOURNAL
Volume 393, Issue -, Pages 343-349Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20051277
Keywords
lipid-protein adduct; neurodegenerative disorder; Parkinson's disease; peroxynitrite; alpha-synuclein; nitration
Categories
Funding
- NATIONAL CANCER INSTITUTE [R01CA095586] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA095586, R01 CA95586] Funding Source: Medline
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Intracellular aggregates of alpha-syn (alpha-synuclein) represent pathoanatomical hallmarks of neurodegenerative disorders (synucleinopathies). The molecular mechanisms underlying alpha-syn aggregation into filamentous inclusions may involve oxidation and nitration of the protein. Whereas the effects of oxidants and nitrating species on soluble alpha-syn have been studied in detail, the effect of these reactive species on alpha-syn associated with lipids is still unknown. In the present paper, we report that alpha-syn bound to small unilamellar liposomes composed of phosphatidyleholine/phosphatidic acid is resistant to oxidation and nitration when compared with soluble alpha-syn. Additionally, increasing concentrations of unsaturated fatty acids diminished the oxidation and nitration of alpha-syn upon exposure to fluxes of peroxynitrite (8-20 mu M (.) min(-1)). To investigate the effect of oxidized lipids on a-syn, the protein was incubated with the bifunctional electrophile 4-HNE [4-hydroxy-2(E)-nonenal]. MS analysis showed the formation of three major products corresponding to the native protein and a-syn plus one or two 4-HNE molecules. Trypsin digestion of the modified protein followed by peptide 'fingerprinting' revealed that 4-HNE modified the peptide E(46)GVV-HGVATVAEK(58). Further analysis of the peptides with liquid chromatography-tandem MS identified the modified residue as His(50). The data indicate that the association of alpha-syn with biological membranes protects the protein from oxidation and nitration and thus diminishes the formation of protein molecules capable of forming aggregates. However, products of lipid peroxidation can also modify alpha-syn, generating novel protein adducts that could serve as biomarkers for documenting oxidative processes in human as well as animal and cellular models of alpha-syn aggregation and pathology.
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