Aldehyde dehydrogenase inhibition generates a reactive dopamine metabolite autotoxic to dopamine neurons

Abstract

SUMMARY The neurotransmitter dopamine (DA) is important for numerous biological functions, including control of movement. Oxidation of DA to highly toxic and reactive species has been hypothesized to contribute to the selective neurodegeneration observed in Parkinson's disease (PD). DA catabolism is initiated by oxidative deamination via monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL). Such metabolism can be problematic as it greatly increases the toxicity of DA by production of DOPAL, known to be a toxic and reactive intermediate. DOPAL undergoes carbonyl metabolism primarily via aldehyde dehydrogenase (ALDH) enzymes to a less toxic acid product. Previous studies from our laboratory have shown that cellular ALDH enzymes are sensitive towards products of oxidative stress and lipid peroxidation, which are thought to be elevated during PD pathogenesis. Inhibition of ALDH and the resulting accumulation of DOPAL are concerning as DOPAL is toxic to dopaminergic cells, readily modifies proteins and causes protein aggregation. In addition, pesticides with association between exposure and PD incidence can interfere with DA metabolism and trafficking and/or ALDH activity, directly or indirectly, yielding elevation of DOPAL. Therefore, impairment of carbonyl metabolism is a potential mechanistic link between cellular insult and generation of a toxic and reactive intermediate endogenous to dopamine neurons.

1H-NMR and HPLC–MS/MS-based global/targeted metabolomic evaluation of Hypericum perforatum L. intervention for menopause

“…By reducing oxidative stress, ALDH2 can reduce body inflammation and cell apoptosis, thereby reducing the incidence of senile diabetes and Parkinson's disease. ALDH2 also exerts a neuroprotective function by inhibiting dopamine degradation, which forms the neurotoxic compound 3,4-dihydroxyphenylacetaldehyde (DOPAL) (Doorn, Florang, Schamp, & Vanle, 2014). Thus, HPL may increase the acetyl coenzyme A level through the activation of ALDH2.…”

Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

“…mitochondrial complex III; (Zhang et al, 2003)). Ziram and several other pesticides also inhibit aldehyde dehydrogenase (ALDH), a mitochondrial enzyme that degrades oxidative metabolites of DA and other toxic species (Doorn et al, 2014, Wey et al, 2012). …”

DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

“…Cytosolic ALDH is also differentially expressed among dopaminergic neurons, and the subpopulation of DA neurons which lack the enzyme is more vulnerable to neurodegeneration8. Exposure to ALDH inhibitors9, such as the fungicide benomyl1011 or disulfiram12, causes DOPAL accumulation and have been associated with an increased risk to develop PD; ALDH-KO mice show a Parkinsonian phenotype, DA neuronal death and DOPAL accumulation13.…”