Cited by 1,103Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsPrion Diseases and Protein Misfolding

Metal-triggered Structural Transformations, Aggregation, and Fibrillation of Human α-Synuclein

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Uversky, Vladimir N., Li, Jie, Fink, Anthony L.·2001·Journal of Biological Chemistry

Abstract

Parkinson's disease involves the aggregation of alpha-synuclein to form fibrils, which are the major constituent of intracellular protein inclusions (Lewy bodies and Lewy neurites) in dopaminergic neurons of the substantia nigra. Occupational exposure to specific metals, especially manganese, copper, lead, iron, mercury, zinc, aluminum, appears to be a risk factor for Parkinson's disease based on epidemiological studies. Elevated levels of several of these metals have also been reported in the substantia nigra of Parkinson's disease subjects. We examined the effect of various metals on the kinetics of fibrillation of recombinant alpha-synuclein and in inducing conformational changes, as monitored by biophysical techniques. Several di- and trivalent metal ions caused significant accelerations in the rate of alpha-synuclein fibril formation. Aluminum was the most effective, along with copper(II), iron(III), cobalt(III), and manganese(II). The effectiveness correlated with increasing ion charge density. A correlation was noted between efficiency in stimulating fibrillation and inducing a conformational change, ascribed to formation of a partially folded intermediate. The potential for ligand bridging by polyvalent metal ions is proposed to be an important factor in the metal-induced conformational changes of alpha-synuclein. The results indicate that low concentrations of some metals can directly induce alpha-synuclein fibril formation.

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  • Ferric iron can, in vitro, catalyse the conversion of α-synuclein from the α-helix to the β-sheet conformation that is present in Lewy bodies.

    “Ferric iron can, in vitro, catalyse the conversion of α-synuclein from the α-helix to the β-sheet conformation that is present in Lewy bodies.113,114”

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Research works printed but not linked: 6

  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. Conway, K. A., Lee, S. J., Rochet, J. C., Ding, T. T., Williamson, R. E., and Lansbury, P. T., Jr. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 571-576
  3. Lomakin, A., Teplow, D. B., Kirschner, D. A., and Benedek, G. B. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 7942-7947
  4. Lomakin, A., Chung, D. S., Benedek, G. B., Kirschner, D. A., and Teplow, D. B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 1125-1129
  5. Uversky, V. N., Karnoup, A. S., Segel, D. J., Doniach, S., and Fink, A. L. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 5480 -5483
  6. Goto, Y., Calciano, L. J., and Fink, A. L. (1990) Proc. Nat. Acad. Sci. U. S. A. 87, 573-577

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Authors
Uversky, V. N., Li, J., & Fink, A. L.
Affiliations
  • Russian Academy of Sciences (RU)
  • University of California, Santa Cruz (US)
Corresponding author
Fink, Anthony L.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2001-11
Volume
276
Issue
47
Pages
44284-44296
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2077044335
Cited by
1,103
References
77
Citations by year
2026: 26 · 2025: 42 · 2024: 33 · 2023: 42 · 2022: 61 · 2021: 52 · 2020: 51 · 2019: 55 · 2018: 44 · 2017: 53 · 2016: 52 · 2015: 45 · 2014: 52 · 2013: 49 · 2012: 51
FWCI
22.18
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons - University of South Florida (University of South Florida) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
alpha-synuclein, Parkinson's disease, metal ions, fibrillation kinetics, protein aggregation, conformational change, Lewy bodies, Lewy neurites, substantia nigra, manganese, copper, iron, cobalt, aluminum, polyvalent metal ions, ligand bridging, folding intermediates, metal exposure
MeSH terms
Circular Dichroism, Humans, Kinetics, Metals, Nerve Tissue Proteins, Parkinson Disease, Parkinson Disease, Secondary, Protein Conformation, Recombinant Proteins, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet, Protein Folding, Metals, Heavy, Synucleins, alpha-Synuclein

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