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 neurons and glial cells in the SN of PD patients may contribute to the generation of oxidative stress,
protein aggregation and neuronal death. However, the mechanisms involved in
iron accumulation remain unclear. In previous studies we excluded a role of
transferrin and its receptor in
iron accumulation while we showed that
lactoferrin receptors were overexpressed in blood vessels and dopaminergic neurons in
Parkinson's disease. We recently also described an increase in the expression 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 increased in the ventral mesencephalon of intoxicated animals, concomitant with
iron accumulation, oxidative stress and dopaminergic cell loss. A mutation in DMT1 that impairs
iron transport protected rodents against
parkinsonism-inducing
neurotoxins MPTP and
6-hydroxydopamine (6-OHDA). This study supports a critical role for DMT1 in
iron-mediated neurodegeneration in PD.