Intracellular aggregates of α-syn (α-synuclein) represent pathoanatomical hallmarks of neurodegenerative disorders (synucleinopathies). The molecular mechanisms underlying α-syn aggregation into filamentous inclusions may involve oxidation and nitration of the protein. Whereas the effects of oxidants and nitrating species on soluble α-syn have been studied in detail, the effect of these reactive species on α-syn associated with lipids is still unknown. In the present paper, we report that α-syn bound to small unilamellar liposomes composed of phosphatidylcholine/phosphatidic acid is resistant to oxidation and nitration when compared with soluble α-syn. Additionally, increasing concentrations of unsaturated fatty acids diminished the oxidation and nitration of α-syn upon exposure to fluxes of peroxynitrite (8–20 μM·min−1). To investigate the effect of oxidized lipids on α-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 α-syn plus one or two 4-HNE molecules. Trypsin digestion of the modified protein followed by peptide ‘finger-printing’ revealed that 4-HNE modified the peptide E46GVVHGVATVAEK58. Further analysis of the peptides with liquid chromatography–tandem MS identified the modified residue as His50. The data indicate that the association of α-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 α-syn, generating novel protein adducts that could serve as biomarkers for documenting oxidative processes in human as well as animal and cellular models of α-syn aggregation and pathology.
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Research Article|
December 12 2005
Interaction with phospholipids modulates α-synuclein nitration and lipid–protein adduct formation
Andrés Trostchansky;
Andrés Trostchansky
*Center for Free Radical and Biomedical Research, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, CP 11800, Montevideo, Uruguay
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Summer Lind;
Summer Lind
†Stokes Research Institute and Department of Pharmacology, Children's Hospital of Philadelphia and the University of Pennsylvania, PA 19104, U.S.A.
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Roberto Hodara;
Roberto Hodara
†Stokes Research Institute and Department of Pharmacology, Children's Hospital of Philadelphia and the University of Pennsylvania, PA 19104, U.S.A.
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Tomoyuki Oe;
Tomoyuki Oe
‡Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, PA 19104, U.S.A.
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Ian A. Blair;
Ian A. Blair
‡Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, PA 19104, U.S.A.
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Harry Ischiropoulos;
Harry Ischiropoulos
†Stokes Research Institute and Department of Pharmacology, Children's Hospital of Philadelphia and the University of Pennsylvania, PA 19104, U.S.A.
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Homero Rubbo;
Homero Rubbo
*Center for Free Radical and Biomedical Research, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, CP 11800, Montevideo, Uruguay
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José M. Souza
José M. Souza
1
*Center for Free Radical and Biomedical Research, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, CP 11800, Montevideo, Uruguay
1To whom correspondence should be addressed (email jsouza@fmed.edu.uy).
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Publisher: Portland Press Ltd
Received:
August 04 2005
Revision Received:
September 01 2005
Accepted:
September 08 2005
Accepted Manuscript online:
September 08 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 393 (1): 343–349.
Article history
Received:
August 04 2005
Revision Received:
September 01 2005
Accepted:
September 08 2005
Accepted Manuscript online:
September 08 2005
Citation
Andrés Trostchansky, Summer Lind, Roberto Hodara, Tomoyuki Oe, Ian A. Blair, Harry Ischiropoulos, Homero Rubbo, José M. Souza; Interaction with phospholipids modulates α-synuclein nitration and lipid–protein adduct formation. Biochem J 1 January 2006; 393 (1): 343–349. doi: https://doi.org/10.1042/BJ20051277
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