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Review
.2020 Feb;127(2):169-177.
doi: 10.1007/s00702-019-02106-9. Epub 2019 Dec 5.

The catecholaldehyde hypothesis: where MAO fits in

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Review

The catecholaldehyde hypothesis: where MAO fits in

David S Goldstein. J Neural Transm (Vienna).2020 Feb.

Erratum in

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.

Keywords: Alpha-synuclein; DOPAL; Dopamine; Monoamine oxidase.

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Figures

Fig. 1
Fig. 1
Overview of the sources and fate of intra-neuronal catecholamines, with emphasis on enzymatic oxidation catalyzed by MAO. Dopamine (DA) is produced in the cytoplasm via tyrosine hydroxylase (TH) acting on tyrosine to form 3,4-dihydroxyphenylalanine (DOPA) and then L-aromatic-amino-acid decarboxylase (LAAAD) acting on DOPA to form dopamine. Most of cytoplasmic DA is taken up into vesicles by way of the vesicular monoamine transporter (VMAT). Dopamine-beta-hydroxylase (DBH) in the vesicles catalyzes the production of norepinephrine (NE) from DA. Cytoplasmic DA is subject to oxidative deamination catalyzed by monoamine oxidase-A (MAO-A) in the outer mitochondrial membrane to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), and NE is deaminated to form 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). DOPAL is converted to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH), and DOPEGAL is converted to 3,4-dihydroxyphenylglycol (DHPG) via aldehyde/aldose reductase (AR). Most of vesicular DA and NE released by exocytosis is taken back up into the cytoplasm via cell membrane transporters—the NET for NE (although DA is a better substrate than NE for uptake via the NET). DOPA can undergo spontaneous oxidation to DOPA-quinone (DOPA-Q), resulting in formation of 5-S-cysteinylDOPA (Cys-DOPA), and DA can undergo spontaneous oxidation to DA-quinone (DA-Q), resulting in formation of 5-S-cysteinylDA (Cys-DA)
Fig. 2
Fig. 2
Alternative routes by which oxidation of cytoplasmic dopamine (DA) may modify alpha-synuclein. Most of cytoplasmic DA is taken up into vesicles via the vesicular monoamine transporter (VMAT); a minority undergoes oxidation, by two routes (red numbers in boxes). In route 1, DA is oxidized to form DA-quinone (DA-Q), with subsequent interactions with alpha-synuclein directly or via various further products of DA-Q, including 5-S-cysteinyldopamine (Cys-DA). In route 2, DA is oxidized enzymatically by monoamine oxidase-A (MAO-A) in the outer mitochondrial membrane to form 3,4-dihydroxyphenylacetaldehyde (DOPAL) and hydrogen peroxide (H2O2). Cu(II) promotes the oxidation of DA and DOPAL. Formation of DA-Q and DOPAL-Q is associated with generation of superoxide radicals (O2−•). DOPAL is metabolized by aldehyde dehydrogenase (ALDH) to form 3,4-dihydroxyphenylacetic acid (DOPAC), which exits the cell
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