ArticleBiochemistry2018
Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology.Neurotoxicology · 2024Review
- Toxic interactions between dopamine, α-synuclein, monoamine oxidase, and genes in mitochondria of Parkinson's disease.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- Role of dopamine in the pathophysiology of Parkinson's disease.Translational neurodegeneration · 2023Review
- Impaired aldehyde detoxification exacerbates motor deficits in an alpha-synuclein mouse model of Parkinson's disease.Brain and behavior · 2023Article
- Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity.International journal of molecular sciences · 2021Article
- Stable expression of the human dopamine transporter in N27 cells as an in vitro model for dopamine cell trafficking and metabolism.Toxicology in vitro : an international journal published in association with BIBRA · 2021Article
- The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know.International journal of molecular sciences · 2021Review
- The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases.Seminars in neurology · 2020Review
- The catecholaldehyde hypothesis: where MAO fits in.Journal of neural transmission (Vienna, Austria : 1996) · 2020Review
- 3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and QuinonizingThe Journal of pharmacology and experimental therapeutics · 2020Article
- Synthetic Evidence of the Amadori-Type Alkylation of Biogenic Amines by the Neurotoxic Metabolite Dopegal.The Journal of organic chemistry · 2020Article
- Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.The Journal of clinical investigation · 2020Article
- Enhanced mitochondrial inhibition by 3,4-dihydroxyphenyl-acetaldehyde (DOPAL)-oligomerized α-synuclein.Journal of neuroscience research · 2019Article
- Observation and Kinetic Characterization of Transient Schiff Base Intermediates by CEST NMR Spectroscopy.Angewandte Chemie (International ed. in English) · 2019Article
- Biogenic Aldehyde-Mediated Mechanisms of Toxicity in Neurodegenerative Disease.Current opinion in toxicology · 2019Article
- Overexpression of Vesicular Monoamine Transporter-2 may Block Neurotoxic Metabolites from Cytosolic Dopamine: a Potential Neuroprotective Therapy for Parkinson's Disease.Clinical pharmacology and translational medicine · 2019Article
- Using mass spectrometry-based methods to understand amyloid formation and inhibition of alpha-synuclein and amyloid beta.Mass spectrometry reviewsReview
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5 authors.
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Abstract
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 cross-links 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 cross-linking. 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 cross-links α-synuclein molecules. Exploiting this two-stage reaction, we use an isotopic labeling approach to show the predominant cross-linking mechanism is an interadduct 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 cross-links in disease-state neurons.
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