Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease
Open accessAbstract
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.
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A contributing factor to the increased iron accumulation in Parkinson's disease might be increased DMT1 activity or decreased ferroxidase activity of ceruloplasmin, both of which would increase total intracellular iron.
“A contributing factor to the increased iron accumulation in Parkinson’s disease might be increased DMT1 activity or decreased ferroxidase activity of ceruloplasmin, both of which would increase total intracellular iron, as reported in an animal model of Parkinson’s disease109 and in patients.131–134”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [109]
Increased amounts of iron were assayed in the brains of both the 6-hydroxydopamine and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal model of Parkinson's disease, consistent with the increased expression of a DMT1 isoform (+IRE) reported in the substantia nigra of patients with Parkinson's disease.
“Increased amounts of iron were assayed in the brains of both the 6-hydroxydopamine and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal model of Parkinson’s disease,109,154 consistent with the increased expression of a DMT1 isoform (+IRE) reported in the substantia nigra of patients with Parkinson’s disease.”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [109]
Overexpression of DMT1 and iron accumulation was noted in the mesencephalon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal models of Parkinson's disease.
“Overexpression of DMT1 and iron accumulation was noted in the mesencephalon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal models of Parkinson’s disease.109”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [109]
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- Authors
- Salazar, J., Mena, N., Hunot, S., Prigent, A., Alvarez-Fischer, D., Arredondo, M., Duyckaerts, C., Sazdovitch, V., Zhao, L., Garrick, L. M., Nuñez, M. T., Garrick, M. D., Raisman-Vozari, R., & Hirsch, E. C.
- Affiliations
- Inserm (FR)
- University of Chile (CL)
- 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;
- University at Buffalo, State University of New York (US)
- Millennium Institute for Cell Dynamics and Biotechnology and Department of Biology, Faculty of Sciences, Universidad de Chile, Las Encinas 3370, Santiago, Chile; and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-11-25
- Volume
- 105
- Issue
- 47
- Pages
- 18578-18583
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2587621
- OpenAlex
- W2022993728
- Cited by
- 409
- References
- 53
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 21 · 2023: 11 · 2022: 20 · 2021: 17 · 2020: 26 · 2019: 20 · 2018: 23 · 2017: 32 · 2016: 17 · 2015: 33 · 2014: 28 · 2013: 28 · 2012: 37
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Universidad de Chile (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- European Commission
- Association France Parkinson
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- Parkinson's disease, DMT1, iron accumulation, dopaminergic neuron loss, substantia nigra, MPTP, 6-hydroxydopamine, oxidative stress, neuroprotection
- MeSH terms
- Solute Carrier Family 11, Member 2, Aged, Aged, 80 and over, Animals, Disease Models, Animal, Dopamine, Humans, Iron, Parkinson Disease, Oxidative Stress, Cation Transport Proteins, Mice
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