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Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization

Nature Chemical Biology volume 2, pages 249–253 (2006)Cite this article

A Corrigendum to this article was published on 01 June 2006

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Abstract

Oxidative stress, inflammation and α-synuclein overexpression1 confer risk for development of α-synucleinopathies—neurodegenerative diseases that include Parkinson disease and Lewy body dementia2. Dopaminergic neurons undergo degeneration in these diseases and are particularly susceptible to oxidative stress because dopamine metabolism itself creates reactive oxygen species3. Intraneuronal deposition of α-synuclein as amyloid fibrils or Lewy bodies is the hallmark of these diseases2. Herein, we demonstrate that concentrations of oxidative cholesterol metabolites derived from reactive oxygen species are elevated in the cortices of individuals with Lewy body dementia relative to those of age-matched controls, and we show that these metabolites accelerate α-synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses α-synuclein4. By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable α-synuclein aggregation, leading to a pathologic cycle.

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Figure 1: Quantification of oxidative cholesterol metabolites in vivo.
Figure 2: Oxidative cholesterol metabolites (2/3) and (4) accelerate α-synuclein fibrilization in vitro, as determined by thioflavin T (TfT) fluorescence, CD spectroscopy and SEC.
Figure 3: Electron microscopy images reveal that oxidative cholesterol metabolites (2/3) and (4) hasten the formation of α-synuclein (αS) fibrils.

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Notes

  1. *Note: In the version of this article initially published, a funding source was omitted. The following statement should be added to the end of the Acknowledgments section: "D.A. Bosco is grateful to the National Institutes of Health for a postdoctoral fellowship. We thank the National Institutes of Health (NS050636), the Skaggs Institute for Chemical Biology and the Lita Annenberg Hazen Foundation for financial support." The error has been corrected in the PDF version of the article.

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Acknowledgements

We thank M. Gao and M. Dendle for purifying recombinant α-synuclein; G.V.W. Johnson (Univ. Alabama) for SHSY5Y cells; R. Troseth and A.D. Wentworth for synthesis of metabolites, help with extractions and NMR and mass spectrometry analyses; E. Head (Institute for Brain Aging and Dementia Tissue Repository for assistance obtaining brain samples); and W. Webb of the mass spectrometry core facility (The Scripps Research Institute) for help with mass spectrometry measurements.*Footnote 1

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Authors and Affiliations

  1. Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Daryl A Bosco, Douglas M Fowler, Qinghai Zhang, Evan T Powers, Paul Wentworth Jr, Richard A Lerner & Jeffery W Kelly

  2. Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Jorge Nieva

  3. Department of Biochemistry, Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom

    Paul Wentworth Jr

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  1. Daryl A Bosco
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  2. Douglas M Fowler
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Correspondence to Jeffery W Kelly.

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Competing interests

J.W.K. is a founder of FoldRx Pharmaceuticals, a company that aspires to discover drugs that ameliorate Parkinson disease.

Supplementary information

Supplementary Fig. 1

Addition of cholesterol metabolites (2/3) and (4) is toxic to SHSY5Y cells, whereas cholesterol is not toxic. (PDF 183 kb)

Supplementary Fig. 2

Electron microscopy (EM) images for control αS aggregation reactions. (PDF 464 kb)

Supplementary Fig. 3

αS catalyzes the conversion of oxidative metabolite (2) into (3) as measured by thin layer chromatography (TLC). (PDF 55 kb)

Supplementary Fig. 4

The hastening of αS fibrilization by (4) is not affected by addition of the competitive Schiff-base inhibitor aminoguanidine. (PDF 88 kb)

Supplementary Table 1

Summary of the temporal biophysical characterization of oxidative cholesterol metabolite hastened αS fibrilization. (PDF 156 kb)

Supplementary Methods (PDF 285 kb)

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Bosco, D., Fowler, D., Zhang, Q. et al. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization. Nat Chem Biol 2, 249–253 (2006). https://doi.org/10.1038/nchembio782

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