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Review
. 2021 Jun 1;22(11):5999.
doi: 10.3390/ijms22115999.

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

David S Goldstein  1
Affiliations
Review

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

David S Goldstein. Int J Mol Sci. .

Abstract

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL-destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could "freeze" intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

Keywords: DOPAL; alpha-synuclein; autotoxicity; catecholaldehyde; dopamine; monoamine oxidase.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Enzymatic and spontaneous oxidation of dopamine. Monoamine oxidase (MAO) in the outer mitochondrial membrane converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), ammonia, and hydrogen peroxide. Dopamine oxidizes spontaneously to dopamine quinone, generating superoxide radical. Dopamine quinone can react SH) to form glutathionyldopamine, which, in the presence of gammaglutamyl transferase (GGT) and dipeptidases, results in the formation of 5-S-cysteinyldopamine (Cys-DA). Cys-DA can also be produced by dopamine quinone reacting with cysteine. Cyclization of dopamine quinone produces leukaminochrome, which can be oxidized to form aminochrome. Reduction of aminochrome yields the indole 5,6-dihydroxyindole. Melanins are formed from polymerization of Cys-DA or 5,6-dihydroxyindole. The relatively thick arrow corresponding to MAO is used to denote that given the alternative spontaneous vs. enzyme-catalyzed oxidation of cytoplasmic dopamine, the enzymatic route would predominate; however, MAO inhibition could increase the formation of spontaneous oxidation products.
Figure 2
Figure 2
Dopamine synthesis, storage, reuptake, and metabolism. Dopamine (DA) is produced in the neuronal 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). This is balanced by passive leakage from the vesicles into the cytoplasm. 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). DOPAL is converted to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). A minor pathway is via aldehyde/aldose reductase (AR) to form 3,4-dihydroxyphenylethanol (DOPET). Most of vesicular DA released by exocytosis is taken back up into the cytoplasm via the cell membrane dopamine transporter (DAT). DA can undergo spontaneous oxidation to DA quinone (DA-Q), resulting in the formation of a variety of oxidation products including 5-S-cysteinyldopamine (Cys-DA).
Figure 3
Figure 3
Norepinephrine synthesis, storage, reuptake, and metabolism. In noradrenergic neurons, dopamine (DA) is produced in the cytoplasm as in dopaminergic neurons. Dopamine-beta-hydroxylase (DBH) in the vesicles catalyzes the production of norepinephrine (NE) from DA. As for DA, cytoplasmic NE is subject to oxidative deamination catalyzed by monoamine oxidase-A (MAO-A) in the outer mitochondrial membrane, to form 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). It should be noted that NE is a poorer substrate than DA for MAO of either isoform. DOPEGAL is converted to 3,4-dihydroxyphenylglycol (DHPG) via aldehyde/aldose reductase (AR). A minor pathway (not shown) involves conversion of DOPEGAL to dihydroxymandelic acid via aldehyde dehydrogenase (ALDH). As for DA, most of vesicular NE released by exocytosis is taken back up into the cytoplasm via a cell membrane transporter—the cell membrane norepinephrine transporter (NET) for NE (although DA is a better substrate than NE for uptake via the NET). Theoretically, NE can be oxidized spontaneously to NE quinone and downstream oxidation products. Other abbreviations: LAAAD = L-aromatic-amino-acid decarboxylase; TH = tyrosine hydroxylase; TYR = tyrosine; VMAT = vesicular monoamine transporter.
Figure 4
Figure 4
Intraneuronal effects of DOPAL buildup. DOPAL buildup in the neuronal cytoplasm may exert numerous harmful effects. These can be classified in terms of cytotoxicity via adverse effects on mitochondria and abnormalities from protein modifications, probably mediated by DOPAL quinone (DOPAL-Q). For instance, DOPAL inhibits tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD). DOPAL can interfere its own detoxification by inhibiting aldehyde dehydrogenase (ALDH). DOPAL also decreases the storage of catecholamines in vesicles, by inhibiting the cell membrane norepinephrine transporter (NET) or the vesicular monoamine transporter (VMAT) or permeabilizing vesicles.
Figure 5
Figure 5
Intracellular quinoproteins produced by 3,4-dihydroxyphenylacetaldehyde (DOPAL). (A): DOPAL-induced quinonization of intracellular proteins in MO3.13 human cultured oligodendrocytes. MO3.13 cells (1.5 × 105 cells/well) were exposed to (A) DOPAL (100 μM) with or without Cu(II) (10 and 30 μM) for 24 h. DOPAL-quinonized proteins were detected and quantified by infrared fluorescence (nIRF) spectroscopy (red). N = number of replicates. DOPAL quinonized myriad intracellular proteins. Cu(II) augmented this effect. (B): Comparisons of dopamine (DA)- vs. DOPAL-induced alpha-synuclein (αS) quinonization. Quinonized αS was detected by near infrared fluorescence (nIRF) spectroscopy (red). Even in the presence of tyrosinase (Tyr) to oxidize DA, DA did not quinonize αS. (C): Visualization of intracellular DOPAL-induced quinoproteins. MO3.13 cells were cultured in slide chambers (8 × 104 cells/slides) for 24 h and treated with Cu(II) (30 μM) and 0–100 μM DOPAL for 5 h. Cells were then stained with DAPI (1:2000) (blue) and human tubulin antibody (1:1500) (green). Immunofluorescence and near infrared fluorescence (nIRF) were visualized microscopically. Scale bar in images is 20 μM. Treatment with DOPAL produced nIRF signals, indicating the presence of quinoproteins. Images are from [122].
Figure 6
Figure 6
Some effects of 3,4-dihydroxyphenylacetaldehyde (DOPAL)-induced modification of alpha-synuclein (αS). Among myriad protein modifications exerted by DOPAL, one of the most prominent is oligomerization of, formation of quinone–protein adducts with (“quinonization”), and aggregation of αS. DOPAL-induced αS oligomers interfere with vesicular functions and are toxic to mitochondria. Not shown, αS may increase DOPAL formation via stimulation of MAO activity. The relative roles of DOPAL alone, αS alone, and their interactions in catecholaminergic neurodegeneration is poorly understood. It is also possible that αS and DOPAL emanating from catecholaminergic neurons can be taken up into non-neuronal glial cells and harm the neurons indirectly via altered glial functions.
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