Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α‐Synuclein

Werner-Allen, Jon W.; DuMond, Jenna F.; Levine, Rodney L.; Bax, Ad

doi:10.1002/ange.201600277

Cited by 13 publications

(8 citation statements)

References 22 publications

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“…Oxidized dopamine metabolites have been reported to form covalent adducts with αS. 59,6061 EGCG has been proposed to form covalent or non-covalent adducts with proteins, 62 including amyloid fibrils. 63 Our preliminary studies with tetramethylated NDGA (mNDGA) indicate that oxidation may indeed be important to disaggregation, as mNDGA, which cannot form o -quinone oxidation products, does not have a substantial effect on αS fibrils (see Supporting Information, Fig.…”

Section: Resultsmentioning

confidence: 99%

Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules

et al. 2016

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Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson’s disease. Here, we show that measuring the fluorescence polarization (FP) of labels at several sites on αS allows one to monitor changes in the local dynamics of the protein after binding to micelles or vesicles, and during fibril formation. Most significantly, these site-specific FP measurements provide insight into structural remodeling of αS fibrils by small molecules and have the potential for use in moderate-throughput screens to identify small molecules that could be used to treat Parkinson’s disease.

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Section: Resultsmentioning

confidence: 99%

Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules

et al. 2016

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“…Since antioxidation with NAC mitigated these AS modifications, the results raise the possibility that oxidation products of DOPAL and DA can polymerize (Lee et al, 2007) and bind to AS, resulting in a large variety of high molecular weight forms of the bound AS. AS oligomers linked by DOPAL condensation products (Werner-Allen et al, 2016, 2017) may also polymerize. These possibilities are not mutually exclusive, and the present data cannot distinguish between them.…”

Section: Discussionmentioning

confidence: 99%

3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein

Jinsmaa

Isonaka

Sharabi

et al. 2019

J Pharmacol Exp Ther

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Lewy body diseases such as Parkinson's disease involve intraneuronal deposition of the protein a-synuclein (AS) and depletion of nigrostriatal dopamine (DA). Interactions of AS with DA oxidation products may link these neurohistopathologic and neurochemical abnormalities via two potential pathways: spontaneous oxidation of DA to dopamine-quinone and enzymatic oxidation of DA catalyzed by monoamine oxidase to form 3,4dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-Q. We compared these two pathways in terms of the ability of DA and DOPAL to modify AS. DOPAL was far more potent than DA both in oligomerizing and forming quinoneprotein adducts with (quinonizing) AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by antioxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intracellular quinoproteins that were visualized by near-infrared spectroscopy. We conclude that of the two routes by which oxidation of DA modifies AS and other proteins the route via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation. SIGNIFICANCE STATEMENT Interactions of the protein a-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson disease: Lewy bodies (which contain abundant AS) and nigrostriatal DA depletion (which produces the characteristic movement disorder). Of the two potential routes by which DA oxidation may alter AS and other proteins, the route via the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPALinduced protein modifications.

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“…Importantly, 11 of 15 Lys residues found in aSyn are located in the N-terminal domain, which is the primary target of DOPAL. 32,56 Taken these findings into account, we suggest that both familial aSyn mutations (at least for A30P, A53T, and H50Q) and the formation of adducts with DOPAL may favor the release of the protein from membrane surfaces and, hence, enhance the susceptibility of the protein to form DOPALinduced oligomers.…”

Section: ■ Results and Discussionmentioning

confidence: 87%

Role of Parkinson’s Disease-Linked Mutations and N-Terminal Acetylation on the Oligomerization of α-Synuclein Induced by 3,4-Dihydroxyphenylacetaldehyde

Lima

Nascimento

Eliezer

et al. 2018

ACS Chem. Neurosci.

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Identifying the mechanisms by which the presynaptic protein α-synuclein (aSyn) is associated to neurodegeneration of dopamine neurons is a major priority in the Parkinson's disease (PD) field. Studies indicate that DOPAL (3,4-dihydroxyphenylacetaldehyde), an aldehyde generated from the enzymatic oxidation of dopamine, may convert aSyn monomer into a neurotoxin via formation of covalently stabilized toxic oligomers. Herein we investigated the role of N-terminal acetylation and familial aSyn mutations (A30P, A53T, E46K, G51D and H50Q) on DOPAL-induced oligomerization of the protein. Our results indicate that wild-type (WT) N-terminally acetylated-aSyn (Ac-aSyn) is less prone to form oligomers upon incubation with DOPAL than the non-Nterminally acetylated protein. On the other hand, familial mutants from Ac-aSyn, particularly A53T, E46K and H50Q increased the formation of DOPAL-derived aSyn oligomers, especially large oligomers. Binding of aSyn to synaptic-like small unilamellar vesicles (SUVs) protected distinctively aSyn variants against the effects of DOPAL. While N-terminal acetylation increased the protective action of against DOPAL-induced aSyn oligomerization, A53T, A30P and H50Q mutations in Ac-aSyn had an opposite effect. It means that PD-linked mutations may not only perturb the affinity of aSyn for membranes but also influence the formation of DOPAL-mediated oligomers. Overall, our findings provide important evidences for the existence of a connection between familial mutations of aSyn, and their distinct affinity to lipid membranes, and the formation of potentially toxic oligomers of the protein mediated by DOPAL.

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Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α‐Synuclein

Cited by 13 publications

References 22 publications

Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules

Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules

3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein

Role of Parkinson’s Disease-Linked Mutations and N-Terminal Acetylation on the Oligomerization of α-Synuclein Induced by 3,4-Dihydroxyphenylacetaldehyde

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