Document Detail

Enhanced autophagy from chronic toxicity of iron and mutant A53T α-synuclein: implications for neuronal cell death in Parkinson disease.
MedLine Citation:
PMID:  21795716     Owner:  NLM     Status:  MEDLINE    
Parkinson disease (PD), a prevalent neurodegenerative motor disorder, is characterized by the rather selective loss of dopaminergic neurons and the presence of α-synuclein-enriched Lewy body inclusions in the substantia nigra of the midbrain. Although the etiology of PD remains incompletely understood, emerging evidence suggests that dysregulated iron homeostasis may be involved. Notably, nigral dopaminergic neurons are enriched in iron, the uptake of which is facilitated by the divalent metal ion transporter DMT1. To clarify the role of iron in PD, we generated SH-SY5Y cells stably expressing DMT1 either singly or in combination with wild type or mutant α-synuclein. We found that DMT1 overexpression dramatically enhances Fe(2+) uptake, which concomitantly promotes cell death. This Fe(2+)-mediated toxicity is aggravated by the presence of mutant α-synuclein expression, resulting in increased oxidative stress and DNA damage. Curiously, Fe(2+)-mediated cell death does not appear to involve apoptosis. Instead, the phenomenon seems to occur as a result of excessive autophagic activity. Accordingly, pharmacological inhibition of autophagy reverses cell death mediated by Fe(2+) overloading. Taken together, our results suggest a role for iron in PD pathogenesis and provide a mechanism underlying Fe(2+)-mediated cell death.
Katherine C M Chew; Eng-Tat Ang; Yee Kit Tai; Fai Tsang; Shun Qiang Lo; Elijah Ong; Wei-Yi Ong; Han-Ming Shen; Kah-Leong Lim; Valina L Dawson; Ted M Dawson; Tuck Wah Soong
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-19     Completed Date:  2011-11-23     Revised Date:  2013-07-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33380-9     Citation Subset:  IM    
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
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MeSH Terms
Apoptosis / drug effects
Autophagy / drug effects*
Cation Transport Proteins / metabolism
Cell Line
Cytochromes c / metabolism
Iron / metabolism,  toxicity*
Mutant Proteins / toxicity*
Neurons / drug effects,  pathology*,  ultrastructure
Oxidative Stress / drug effects
Parkinson Disease / pathology*
Phagosomes / drug effects,  metabolism,  ultrastructure
Proteasome Endopeptidase Complex / metabolism
Ubiquitin / metabolism
alpha-Synuclein / toxicity*
Reg. No./Substance:
0/Cation Transport Proteins; 0/Mutant Proteins; 0/Ubiquitin; 0/alpha-Synuclein; 0/solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2; 7439-89-6/Iron; 9007-43-6/Cytochromes c; EC Endopeptidase Complex

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