Cited by 275Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNuclear Receptors and Signaling

Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations

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Norris, Erin H., Giasson, Benoit I., Hodara, Roberto, Xu, Shaohua, Trojanowski, John Q., Ischiropoulos, Harry, Lee, Virginia M.-Y.·2005·Journal of Biological Chemistry

Abstract

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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  1. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., and Goedert, M. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6469 -6473
  2. Serpell, L. C., Berriman, J., Jakes, R., Goedert, M., and Crowther, R. A. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 4897-4902
  3. Lee, M. K., Stirling, W., Xu, Y., Xu, X., Qui, D., Mandir, A. S., Dawson, T. M., Copeland, N. G., Jenkins, N. A., and Price, D. L. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 8968 -8973
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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.
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
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 › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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