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

TLDR

Parkinson’s disease is marked by dopaminergic cell loss in the substantia nigra, with iron accumulation in neurons and glia thought to drive oxidative stress, protein aggregation, and neurodegeneration, though the underlying mechanisms remain unclear. The study investigates increased expression of a DMT1 isoform in the substantia nigra of Parkinson’s disease patients. Using an MPTP mouse model, the authors showed that DMT1 expression rises together with iron buildup, oxidative stress, and dopaminergic neuron loss in the ventral mesencephalon. A DMT1 mutation that impairs iron transport protects rodents from MPTP and 6‑hydroxydopamine toxicity, highlighting DMT1’s critical role in iron‑mediated neurodegeneration in Parkinson’s disease.

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.