Oxidative Stress and Redox Signalling in Parkinson’s Disease
CHAPTER 4: Dopamine Metabolism and the Generation of a Reactive Aldehyde
Published:21 Jul 2017
J. H. Schamp and J. A. Doorn, in Oxidative Stress and Redox Signalling in Parkinson’s Disease, ed. R. Franco, J. A. Doorn, and J. Rochet, The Royal Society of Chemistry, 2017, pp. 97-115.
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Dopamine (DA) is a monoamine neurotransmitter important for the control of movement. When not sequestered in vesicles, DA is metabolized by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which can further undergo metabolism by aldehyde dehydrogenases (ALDH) and aldehyde/aldose reductases (AR) to 3,4-dihydroxyphenylacetic acid, and 3,4-dihydroxyphenylethanol, respectively. Other monoamines such as norepinephrine and serotonin also are metabolized by MAO, yielding biogenic aldehydes. DOPAL has been shown to be toxic to dopaminergic cells at levels close to those measured for physiologic conditions. Generation of the DA-derived aldehyde at aberrant levels could be due to several mechanisms, including: inhibition of ALDH and AR via oxidative stress products, impairment of DA trafficking, and direct inhibition of carbonyl metabolism. Models of altered DA metabolism or trafficking demonstrate toxic endpoints and/or progressive loss of DA neurons, indicating that proper DA metabolism and trafficking is critical for health of DA neurons. DOPAL is a highly reactive aldehyde intermediate that modifies proteins and causes protein aggregation. In addition, the DA-derived aldehyde can auto-oxidize to a quinone, producing reactive oxygen species (ROS), and generates ROS during the reaction with proteins. Given such evidence, DOPAL is hypothesized to be an endogenous neurotoxin and mechanistic link between exposure or insults and conditions relevant to neurodegenerative disease.