Abstract
Monoamine oxidase (MAO) plays a central role in the metabolism of the neurotransmitters dopamine, norepinephrine, and serotonin. This brief review focuses on 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is the immediate product of MAO acting on cytoplasmic dopamine. DOPAL is toxic; however, normally DOPAL is converted via aldehyde dehydrogenase (ALDH) to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. In addition to vesicular uptake of dopamine via the vesicular monoamine transporter (VMAT), the two-enzyme sequence of MAO and ALDH keeps cytoplasmic dopamine levels low. Dopamine oxidizes readily to form toxic products that could threaten neuronal homeostasis. The catecholaldehyde hypothesis posits that diseases featuring catecholaminergic neurodegeneration result from harmful interactions between DOPAL and the protein alpha-synuclein, a major component of Lewy bodies in diseases such as Parkinson disease, dementia with Lewy bodies, and pure autonomic failure. DOPAL potently oligomerizes alpha-synuclein, and alpha-synuclein oligomers impede vesicular functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—a vicious cycle. When MAO deaminates dopamine to form DOPAL, hydrogen peroxide is generated; and DOPAL, hydrogen peroxide, and divalent metal cations react to form hydroxyl radicals, which peroxidate lipid membranes. Lipid peroxidation products in turn inhibit ALDH, causing DOPAL to accumulate—another vicious cycle. MAO inhibition decreases DOPAL formation but concurrently increases the spontaneous oxidation of dopamine, potentially trading off one form of toxicity for another. These considerations rationalize a neuroprotection strategy based on concurrent treatment with an MAO inhibitor and an anti-oxidant.
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21 December 2019
The original version of this article unfortunately contained a mistake. The presentation of Figure 1 was incorrect. The corrected Figure 1 is given below.
Abbreviations
- ALDH:
-
Aldehyde dehydrogenase
- AS:
-
Alpha-synuclein
- Cys-DA:
-
5-S-Cysteinyldopamine
- DLB:
-
Dementia with Lewy bodies
- DOPAC:
-
3,4-Dihydroxyphenylacetic acid
- DOPAL:
-
3,4-Dihydroxyphenylacetaldehyde
- DOPAL-Q:
-
DOPAL-quinone
- LAAAD:
-
L-Aromatic-amino-acid decarboxylase
- MSA:
-
Multiple system atrophy
- NE:
-
Norepinephrine
- NET:
-
Cell membrane norepinephrine transporter
- nOH:
-
Neurogenic orthostatic hypotension
- OH:
-
Orthostatic hypotension
- PAF:
-
Pure autonomic failure
- PD:
-
Parkinson disease
- TH:
-
Tyrosine hydroxylase
- VMAT:
-
Vesicular monoamine transporter
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Research reported in this review was supported (in part) by the Intramural Research Program of the NIH, NINDS.
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Goldstein, D.S. The catecholaldehyde hypothesis: where MAO fits in. J Neural Transm 127, 169–177 (2020). https://doi.org/10.1007/s00702-019-02106-9
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DOI: https://doi.org/10.1007/s00702-019-02106-9