Letter abstract
Nature Chemical Biology 2, 249 - 253 (2006)
Published online: 26 March 2006 | Corrected online: 8 May 2006 | doi:10.1038/nchembio782
There is a Corrigendum (June 2006) associated with this Letter.
Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate 
-synuclein fibrilization
Daryl A Bosco1, Douglas M Fowler1, Qinghai Zhang1, Jorge Nieva2, Evan T Powers1, Paul Wentworth, Jr1,3, Richard A Lerner1 & Jeffery W Kelly1
Oxidative stress, inflammation and 
-synuclein overexpression1 confer risk for development of -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 -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 -synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses -synuclein4. By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable -synuclein aggregation, leading to a pathologic cycle.
- Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
- Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
Correspondence to: Jeffery W Kelly1 e-mail: jkelly@scripps.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
α-synuclein and cytosolic dopamine: Stabilizing a bad situationNature Medicine News and Views (01 Dec 2001)
Protofibrils, the unifying toxic molecule of neurodegenerative disorders?Nature Neuroscience News and Views (01 Sep 2001)
See all 3 matches for News And ViewsRESEARCH
EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomersNature structural & molecular biology Article (01 Jun 2008)
See all 25 matches for Research