Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Abstract

Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

Keywords: Alpha-synuclein; Autotoxicity; Catecholamine; DOPAL; Parkinson disease.

Fig. 1

Overview of putative pathways of catecholamine autotoxicity in a dopaminergic neuron. Dopamine (DA) is formed in the cytosol from the action of L-aromatic-amino-acid decar-boxylase (LAAAD) on DOPA, which is the immediate product of the rate-limiting enzymatic step in DA synthesis, hydroxylation of tyrosine mediated by tyrosine hydroxylase (TH). Cytosolic DA can auto-oxidize spontaneously or undergo enzymatic oxidation catalyzed by monoamine oxidase-A (MAO-A) in the outer mitochondrial membrane; however, the main fate of cytosolic DA is vesicular uptake via the type 2 vesicular monoamine transporter (VMAT2). Vesicular DA (DA_V) can leak from the vesicles into the cytosol or undergo exocytotic release. Most of released DA is taken back up into the cytosol via the cell membrane DA transporter (DAT). The action of MAO-A on cytosolic DA yields hydrogen peroxide (H₂O₂) and 3,4-dihydroxyphenylacetaldehyde (DOPAL). H₂O₂ reacts with metal ions to produce reactive oxygen species (in this case hydroxyl ions), resulting in oxidative injury including peroxidation of lipid membranes. DOPAL cross-links with amino acids in proteins; this can inactivate enzymes (e.g., TH) and transporters. DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH) to form 3,4-dihydroxyphenylacetic acid (DOPAC). A minor pathway of metabolism (not shown) is enzyme-catalyzed reduction to form 3,4-dihydroxyphenylethanol. Stimulatory relationships are indicated by (+) and inhibitory relationships by (−). De-stabilizing positive feedback loops are indicated when all signs in a loop are +.

Fig. 2

Putative toxic interactions between DOPAL and alpha-synucleinopathy in a dopaminergic neuron. According to the autotoxicity concept, DOPAL and alpha-synuclein are nodes in a complex pathogenetic nexus. DOPAL oligomerizes alpha-synuclein, rendering the protein toxic. Divalent metal cations augment DOPAL-induced oligomerization of alpha-synuclein.

Fig.3

Potential mechanisms of synucleinopathy-induced augmentation of DOPAL production. Synucleinopathy might increase DOPAL formation by inhibiting VMAT2 expression or functions, permeabilizing vesicles, interfering with axonal transport (thereby decreasing vesicle numbers in striatal dopaminergic terminals), and inhibiting exocytosis.

Fig. 4

Potential sites of interaction between genotypic abnormalities and catecholamine autotoxicity. See text for meanings of abbreviations.