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Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations
Open accessAbstract
Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346-1349). Dopamine inhibition of alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/renaturation. Taken together, these data indicate that dopamine inhibits alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.
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“Aminochrome is a highly reactive molecule capable of forming adducts with α-synuclein and ROS such as superoxide radical anion and depleting NADPH (Norris et al. 2005).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Norris et al. 2005
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Metadata
- Authors
- Norris, E. H., Giasson, B. I., Hodara, R., Xu, S., Trojanowski, J. Q., Ischiropoulos, H., & Lee, V. M.-Y.
- Affiliations
- Institute on Aging (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Lee, Virginia M.-Y.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 280
- Issue
- 22
- Pages
- 21212-21219
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1975188689
- Cited by
- 273
- References
- 51
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 12 · 2022: 8 · 2021: 14 · 2020: 9 · 2019: 21 · 2018: 14 · 2017: 8 · 2016: 5 · 2015: 17 · 2014: 17 · 2013: 15 · 2012: 13
- FWCI
- 11.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NS044233, AG-09215)
- National Institute on Aging (AG09215, P01AG009215)
- National Institute of Neurological Disorders and Stroke (P01NS044233, NS-044233)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, fibrillization, dopamine autoxidation, conformational change, Parkinson's disease, dopaminergic neurons, substantia nigra, protein aggregation
- MeSH terms
- Circular Dichroism, Dopamine, Histidine, Humans, Methionine, Microscopy, Electron, Mutation, Nerve Tissue Proteins, Oxygen, Parkinson Disease, Peptides, Protein Conformation, Recombinant Proteins, Time Factors, Tyrosine, Mutagenesis, Protein Structure, Secondary, Spectroscopy, Fourier Transform Infrared, DNA, Complementary, Oxidative Stress, Microscopy, Atomic Force, Amino Acid Motifs, Indolequinones, Synucleins, alpha-Synuclein
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