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

Goldstein, David S.; Kopin, Irwin J.; Sharabi, Yehonatan

doi:10.1016/j.pharmthera.2014.06.006

Cited by 138 publications

(133 citation statements)

References 222 publications

(277 reference statements)

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“…2 DOPAL may exert its toxicity by forming adducts with α-synuclein that disrupt its cellular function and localization, for example by impairing its membrane binding, 34, 35 and by catalyzing covalent crosslinks that nucleate toxic oligomeric species or stabilize them, possibly by terminating in-register fibril elongation. Despite the potential importance of the catecholaldehyde hypothesis in PD etiology, the products of DOPAL reactivity remain poorly characterized in comparison with protein modification by other small molecules.…”

Section: Discussionmentioning

confidence: 99%

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Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

et al. 2018

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3,4-dihydroxyphenylacetaldehyde (DOPAL) is a toxic and reactive product of dopamine catabolism. In the catecholaldehyde hypothesis for Parkinson’s disease, it is a critical driver of the selective loss of dopaminergic neurons that characterizes the disease. DOPAL also crosslinks α-synuclein, the main component of Lewy bodies, which are a pathological hallmark of the disease. We previously described the initial adduct formed in reactions between DOPAL and α-synuclein, a dicatechol pyrrole lysine (DCPL). Here, we examine the chemical basis for DOPAL-based crosslinking. We find that autoxidation of DCPL’s catechol rings spurs its decomposition, yielding an intermediate dicatechol isoindole lysine (DCIL) product formed by an intramolecular reaction of the two catechol rings to give an unstable tetracyclic structure. DCIL then reacts with a second DCIL to give a dimeric, di-DCIL. This product is formed by an intermolecular carbon-carbon bond between the isoindole rings of the two DCILs that generates two structurally nonequivalent and separable atropisomers. Using α-synuclein, we demonstrate that the DOPAL-catalyzed formation of oligomers can be separated into two steps. The initial adduct formation occurs robustly within an hour, with DCPL as the main product, and the second step crosslinks α-synuclein molecules. Exploiting this two-stage reaction, we use an isotopic labeling approach to show the predominant crosslinking mechanism is an inter-adduct reaction. Finally, we confirm that a mass consistent with a di-DCIL linkage can be observed in dimeric α-synuclein by mass spectrometry. Our work elucidates previously unknown pathways of catechol-based oxidative protein damage and will facilitate efforts to detect DOPAL-based crosslinks in disease-state neurons.

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Section: Discussionmentioning

confidence: 99%

“…26 – 28 Reactive endogenous small molecules and environmental toxins are known to promote covalent α-synuclein crosslinking, and their potential to nucleate and/or stabilize toxic oligomeric species has sparked recent efforts to define their roles in PD. 2, 14, 29 – 31 …”

Section: Introductionmentioning

confidence: 99%

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

et al. 2018

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“…Since DA is synthesized in the neuronal cytoplasm, a vesicular storage defect in putamen terminals could promote accumulation of cytoplasmic DA and consequently increase formation of cytotoxic products of DA metabolism [33, 39–41]. There are two general mechanisms by which buildup of cytoplasmic catecholamine may contribute to the death of catecholamine neurons.…”

Section: Implications For the Pathogenesis Of Pd And Related Disordersmentioning

confidence: 99%

Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration

Goldstein¹,

Holmes²,

Sullivan³

et al. 2015

Parkinsonism & Related Disorders

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Several neurodegenerative diseases involve loss of catecholamine neurons—Parkinson’s disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of “autotoxicity”—inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of 18F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of 18F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen 18F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial 18F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons.

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“…To explain the vulnerability of catecholamine neurons in Parkinson's disease, we have proposed "autotoxicity"-inherent cytotoxicity of catecholamine metabolites (Goldstein et al, 2014)-which is probably a contributory pathogenetic mechanism. In neurons, cytoplasmic DA is converted to 3,4-dihydroxyphenylacetaldehyde (DOPAL) by monoamine oxidase-A (MAO-A; Fig.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

Goldstein

Jinsmaa

Sullivan

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson's disease.

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

Cited by 138 publications

References 222 publications

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration

Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

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