title: L-DOPA is incorporated into brain proteins of patients treated for Parkinson's disease, inducing toxicity in human neuroblastoma cells in vitro.
abstract: Levodopa (L-DOPA), a close structural analogue of the protein amino acid L-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.
authors: The Cell Biology Group, The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, NSW 2042, Australia.
authors: Sandra W
authors: SW
authors: Chan
authors: Rachael A
authors: RA
authors: Dunlop
authors: Anthony
authors: A
authors: Rowe
authors: Kay L
authors: KL
authors: Double
authors: Kenneth J
authors: KJ
authors: Rodgers
mesh_terms: D000978:Antiparkinson Agents / Q000378:metabolism* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001797:Blood Protein Electrophoresis; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D053938:DNA Fragmentation; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism* / Q000633:toxicity*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D051336:Mitochondrial Membranes / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D011804:Quinolines
chemical_list: D000978:Antiparkinson Agents; D007202:Indicators and Reagents; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011804:Quinolines; D007980:Levodopa; C047117:bicinchoninic acid; D007770:L-Lactate Dehydrogenase; D020169:Caspases