Cellular deposits of oxidized and aggregated proteins are hallmarks of a variety of age-related disorders, but whether such proteins contribute to pathology is not well understood. We previously reported that oxidized proteins form lipofuscin/ceroid-like bodies with a lysosomal-type distribution and up-regulate the transcription and translation of proteolytic lysosomal enzymes in cultured J774 mouse macrophages. Given the recently identified role of lysosomes in the induction of apoptosis, we have extended our studies to explore a role for oxidized proteins in apoptosis. Oxidized proteins were biosynthetically generated in situ by substituting oxidized analogues for parent amino acids. Apoptosis was measured with Annexin-V/PI (propidium iodide), TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling), MMP (mitochondrial membrane permeabilization), caspase activation and cytochrome c release, and related to lysosomal membrane permeabilization. Synthesized proteins containing the tyrosine oxidation product L-DOPA (L-3,4-dihydroxyphenylalanine) were more potent inducers of apoptosis than proteins containing the phenylalanine oxidation product o-tyrosine. Apoptosis was dependent upon incorporation of oxidized residues, as indicated by complete abrogation in cultures incubated with the non-incorporation control D-DOPA (D-3,4-dihydroxyphenylalanine) or when incorporation was competed out by parent amino acids. The findings of the present study suggest that certain oxidized proteins could play an active role in the progression of age-related disorders by contributing to LMP (lysosomal membrane permeabilization)-initiated apoptosis and may have important implications for the long-term use of L-DOPA as a therapeutic agent in Parkinson's disease.
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Research Article|
March 15 2011
Proteins containing oxidized amino acids induce apoptosis in human monocytes
Rachael A. Dunlop;
Rachael A. Dunlop
1
*Cell Biology Group, Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia
1To whom correspondence should be addressed (email dunlopr@hri.org.au).
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Ulf T. Brunk;
Ulf T. Brunk
†Division of Pharmacology, Faculty of Health Sciences, University of Linköping, Linköping SE-581 85, Sweden
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Kenneth J. Rodgers
Kenneth J. Rodgers
*Cell Biology Group, Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia
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Publisher: Portland Press Ltd
Received:
May 05 2010
Revision Received:
December 07 2010
Accepted:
January 07 2011
Accepted Manuscript online:
January 07 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 435 (1): 207–216.
Article history
Received:
May 05 2010
Revision Received:
December 07 2010
Accepted:
January 07 2011
Accepted Manuscript online:
January 07 2011
Citation
Rachael A. Dunlop, Ulf T. Brunk, Kenneth J. Rodgers; Proteins containing oxidized amino acids induce apoptosis in human monocytes. Biochem J 1 April 2011; 435 (1): 207–216. doi: https://doi.org/10.1042/BJ20100682
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