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Toxic dopamine metabolites and oxidative stress as key contributors to neurotoxicity (LB641)
Author(s) -
Schamp Josephine,
Florang Virginia,
Doorn Jonathan
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb641
Subject(s) - neurodegeneration , oxidative stress , reactive oxygen species , dopamine , dopaminergic , neurotoxicity , chemistry , biochemistry , 3,4 dihydroxyphenylacetic acid , pharmacology , biology , medicine , neuroscience , serotonin , toxicity , homovanillic acid , receptor , disease , organic chemistry
Toxic dopamine metabolites and reactive oxygen species (ROS) are hypothesized to contribute to progressive neurodegeneration as seen in Parkinson’s Disease (PD). The objective of this study is to explore the role of these mediators (i.e., ROS, reactive intermediates of dopamine metabolism) in neurodegeneration/neurotoxicity. Dopamine (DA), a neurotransmitter, is metabolized via monoamine oxidase to 3, 4‐ dihydroxyphenylacetaldehyde (DOPAL), a highly reactive aldehyde species, and H 2 O 2 . The DA metabolite DOPAL has proven to be toxic to dopaminergic cells both in vitro and in vivo . DOPAL modifies proteins and causes protein aggregation, which may contribute to cell death. We have found a complex interaction between DOPAL and ROS. 1) Like DA, DOPAL undergoes autooxidation to a semiquinone radical and then to an orthoquinone under normal physiological conditions. These quinones are reactive to proteins, as well as produce ROS/oxidative stress (OxS). 2) OxS was determined to increase levels of DOPAL due to inhibition of carbonyl metabolizing enzymes. 3) It has been shown that antioxidants, such as N‐acetylcysteine and ascorbate, can block protein modification by DOPAL. During DOPAL‐mediated protein modification ROS are produced. Using in vitro studies of dopaminergic cells, we found that modulating antioxidant levels regulates the level of DOPAL‐protein adduction. 4) Evidence suggests that the presence of oxygen catalyzes protein modification by DOPAL, resulting in subsequent elevation of ROS. Such data will help elucidate the complex role of OxS, specifically ROS production, in DOPAL‐mediated neurotoxicity and may provide therapeutic targets to prevent or delay neurodegeneration. Grant Funding Source : NIH R01 ES15507; NIH T32 GM067795