Excess iron in neurons is involved in Parkinson's disease

October 28 2008

 

Limiting excess iron in dopaminergic neurons may protect against Parkinson's disease. This is the conclusion of studies carried out by Etienne Hirsch, CNRS research director and his team of researchers in Inserm-UPMC/Université Pierre et Marie Curie Mixed Unit 67 “Neurologie et Thérapeutique Expérimentale” and published in the journal PNAS. They showed that affected rodents over-express DMT1, responsible for iron uptake by neurons. This causes iron accumulation and the death of the neurons. The researchers therefore inhibited the activity of this transporter in order to evaluate the consequences on the disease. Mutant mice were twice less affected by the disease than controls.

Parkinson's disease represents the second neurodegenerative disorder after Alzheimer's disease in France. It is caused by the degeneration of dopaminergic neurons in a precise area of the brain called the substantia nigra. Affected patients therefore develop tremors and stiffness and their movements are slowed.

The causes of the disease are still poorly understood. However, examination of the brains of patients who died with the disease have shown that the degenerating neurons contain a very high iron content compared to normal levels. Iron is essential for the correct functioning of the body, but at high concentrations it damages cell components. “Iron accumulation causes oxidative stress which destroys lipids and proteins in particular and causes cell death. We therefore suspected that an iron excess may be involved in the degeneration of neurons in affected patients,” pointed out Etienne Hirsch, director of the Inserm-Université Pierre et Marie Curie unit.

To clarify this point, the researchers tried to understand how iron accumulated to such high levels in diseased cells. They rapidly orientated their research towards DMT1, which is responsible for neuronal iron uptake. The first stage of their work consisted in chemically inducing Parkinson's disease in mice in order to observe the possible consequences on the expression of these transporters. They noted that their numbers doubled in affected mice in only one to two days after the injection. In parallel, there was a very large increase in the iron concentration of nerve cells, causing a predictable oxidative stress followed by neuronal death after five days.

After obtaining this result, the researchers wanted to observe the effect caused by inhibition of this transporter in rodents. They therefore studied mice in which the activity of DMT1 was greatly impaired and subjected these rodents to a toxin causing Parkinson's disease. These rodents resisted the disease much better than control mice. They were two times less affected, suggesting that the damage to the transporter protected them from the effect of the toxin. “These results are quite conclusive. We have shown that by inhibiting the activity of DMT1, we protected rodents from the disease,” concluded Etienne Hirsch.


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Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease
Julio Salazara,b,c, Natalia Menac, Stephane Hunota,b, Annick Prigenta,b, Daniel Alvarez-Fischera,b, Miguel
Arredondoc, Charles Duyckaertsa,b, Veronique Sazdovitcha,b, Lin Zhaod, Laura M. Garrickd, Marco T. Nun˜ ezc,
Michael D. Garrickd, Rita Raisman-Vozaria,b, and Etienne C. Hirscha,b

(a) Neurologie et Thérapeutique Expérimentale, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S679, 47 Boulevard de l’Hôpital, 75013 Paris, France;
(b) Unité Mixte de Recherche S679, Université Pierre et Marie Curie–Université Paris 6, Boulevard de l’Hôpital, 75013 Paris, France;
(c) Millennium Institute for Cell Dynamics and Biotechnology and Department of Biology, Faculty of Sciences, Universidad de Chile, Las Encinas 3370, Santiago, Chile;
(d) Department of Biochemistry, University at Buffalo, State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214
PNAS, October 27th

Researcher contact
Etienne Hirsch
Inserm Unit 679 – Université Pierre et Marie Curie “Neurologie et Thérapeutique
Expérimentale”
Phone: 01 42 16 22 02

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