Journal
EXPERIMENTAL NEUROLOGY
Volume 238, Issue 1, Pages 29-37Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2011.09.029
Keywords
L-DOPA; Protein; Incorporation; Parkinson's disease; L-tyrosine
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Funding
- National Health and Medical Research Council of Australia
- Neuroscience Research Australia
- University of New South Wales
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Levodopa (L-DOPA), a close structural analogue of the protein amino acid I.-tyrosine, can substitute for L-tyrosine in protein synthesis and be mistakenly incorporated into newly synthesised proteins in vitro. We show that L-DopA-containing proteins are present in the brain in L-DOPA-treated Parkinson's disease patients and accumulate in specific brain regions. In vitro studies demonstrate that substitution of L-tyrosine residues in proteins with L-DOPA causes protein misfolding and promotes protein aggregation in SH-SY5Y neuroblastoma cells resulting in the appearance of autofluorescent bodies. We show that the presence of L-DOPA-containing proteins causes profound changes in mitochondria and stimulates the formation of autophagic vacuoles in cells. Unlike L-DOPA, which is toxic to cells through its ability to generate radicals, proteins containing incorporated L-DOPA are toxic to SH-SY5Y cells by a mechanism independent of oxidative stress and resistant to antioxidants. These data suggest that the accumulation of L-DOPA-containing proteins in vulnerable cells might negatively impact on cell function. (c) 2011 Elsevier Inc. All rights reserved.
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