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.
Highlights
The “catecholaldehyde hypothesis” offers a unitary answer to four key questions about the pathogenesis of Parkinson’s disease (PD) and related Lewy body diseases: (1) only a very small percent of neurons are catecholaminergic
Since monoamine oxidase (MAO) is required for DOPAL formation, a seemingly straightforward test of the catecholaldehyde hypothesis would be to assess whether MAO inhibitors slow the progression of PD; results of large multi-center trials of the MAO-B inhibitors deprenyl and rasagiline failed to demonstrate efficacy convincingly [165,166,167,168,169]
DOPAL formed within catecholaminergic neurons acts as an autotoxin
Summary
The “catecholaldehyde hypothesis” offers a unitary answer to four key questions about the pathogenesis of Parkinson’s disease (PD) and related Lewy body diseases: (1) only a very small percent of neurons are catecholaminergic. (3) Why does the protein alpha-synuclein (αS) tend to precipitate in catecholaminergic neurons in Lewy body diseases? DOPAL is formed from dopamine in the neuronal cytoplasm via enzymatic deamination catalyzed monoamine oxidase (MAO) (Figure 1). The starting point in presenting the catecholaldehyde hypothesis is the role of MAO in DOPAL production [1]. Cyclization of dopamine quinone produces leukaminochrome, which can be oxidized to form aminochrome. 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; MAO inhibition could increase the formation of spontaneous oxidation products
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