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PMID: 19011085 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 47 ·2008-11-25 ·Pages 18578-83

Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nuñez MT, Garrick MD, Raisman-Vozari R, Hirsch EC

Abstract

Dopaminergic cell death in the substantia nigra (SN) is central to Parkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.

MeSH Terms
Aged Aged, 80 and over Animals Cation Transport Proteins/physiology Disease Models, Animal Dopamine/metabolism Humans Iron/metabolism Mice Oxidative Stress Parkinson Disease/metabolism,pathology,physiopathology
Chemicals
Cation Transport Proteins solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2 Iron Dopamine
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Salazar Julio
Institut National de la Santé et de la Recherche Médicale, Neurologie et Thérapeutique Expérimentale, Unité Mixte de Recherche S679, 47 Boulevard de l'Hôpital, 75013 Paris, France.
Mena Natalia
Hunot Stephane
Prigent Annick
Alvarez-Fischer Daniel
Arredondo Miguel
Duyckaerts Charles
Sazdovitch Veronique
Zhao Lin
Garrick Laura M
Nuñez Marco T
Garrick Michael D
Raisman-Vozari Rita
Hirsch Etienne C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0804373105
Published
2008-11-25
Epub
2008-00-14
Pages
18578-83
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2587621
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0804373105 PMC Full Text View journal details
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