Linking Stress, Catecholamine Autotoxicity, and Allostatic Load with Neurodegenerative Diseases: A Focused Review in Memory of Richard Kvetnansky

Abstract

In this Focused Review, we provide an update about evolving concepts that may link chronic stress and catecholamine autotoxicity with neurodegenerative diseases such as Parkinson's disease. Richard Kvetnansky's contributions to the field of stress and catecholamine systems inspired some of the ideas presented here. We propose that coordination of catecholaminergic systems mediates adjustments maintaining health and that senescence-related disintegration of these systems leads to disorders of regulation and to neurodegenerative diseases such as Parkinson's disease. Chronically repeated episodes of stress-related catecholamine release and reuptake, with attendant increases in formation of the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde, might accelerate this process.

Keywords: Allostasis; Autonomic; Biocybernetics; Homeostasis; Stress.

Fig. 1

Overview of the catecholamine autotoxicity theory. The autotoxicity theory explains PD in terms of toxic effects of products of enzymatic and spontaneous oxidation of cytoplasmic dopamine. In particular, enzymatic oxidation of DA to DOPAL and spontaneous oxidation of DOPAL to DOPAL-quinone (DOPAL-Q) exerts toxic effects by generating reactive oxygen species and by modifying functions of a variety of intracellular proteins. Stress-related augmented release of catecholamines and consequently increased neuronal reuptake in effect shift intra-neuronal catecholamines from the vesicles, where they are inert, to the cytoplasm, where they can be rendered cytotoxic. Compensatorily increased traffic to residual terminals sets the stage for induction of lethal positive feedback loops

Fig. 2

Positive feedback loops related to catecholamine autotoxicity in dopaminergic neurons. Dopamine (DA) is formed in the cytosol from the action of l-aromatic-amino-acid decarboxylase (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 (plus) and inhibitory relationships by (minus). De-stabilizing positive feedback loops are indicated when all signs in a loop are +

Fig. 3

Conceptual model relating stress-induced catecholamine release to autotoxicity, allostatic load, and progression of neurodegeneration in Parkinson’s disease. The green (+) signs indicate positive relationships and red (−) signs negative relationships (Color figure online)