Iron transport in Parkinson's disease

https://doi.org/10.1016/S1353-8020(09)70816-8Get rights and content

Summary

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.

Section snippets

Oxidative stress in Parkinson's disease

Parkinson's disease (PD) is characterized from a neuropathological standpoint by the degeneration of dopaminergic neurons in the mesencephalon and the presence of intracytoplasmic inclusions called Lewy bodies [1]. Apart from rare inherited forms of the disease, the cause of PD has still not been identified [2]. Several different, though not mutually exclusive, mechanisms may participate in the cascade of events leading to neuronal degeneration in PD [3]. These changes include accumulation of

Iron transport in Parkinson's disease

Several mechanisms may account for iron penetration into the brain (Fig. 1). The best known mechanism involves the binding of iron-loaded transferrin to its receptor and its translocation to the intracellular compartment [14]. This transporter has been found to be expressed at the level of endothelial cells and may account for iron penetration into the brain parenchyma. Transferrin receptors have also been detected on the plasma membrane of neurons and glial cells. Thus, this mechanism may

Unanswered questions about iron metabolism in Parkinson's disease

In most cellular organisms, iron levels are tightly regulated at both transcriptional and post-transcriptional levels. Indeed, intra-cellular free iron is controlled by ferritin, the major iron storage protein. Two cytoplasmic proteins, iron regulatory proteins 1 and 2 (IRP1 and IRP2) control the synthesis of ferritin by binding to a stem-loop structure located in the 5′ untranslated region of ferritin mRNA known as IRE. When the concentration of iron is low, IRPs bind to the IRE which blocks

Conflict of interests

Research contracts not related to the topic of this article with Laboratoires Fournier-Solvay, Laboratoires Pierre Fabre, Institut de recherche International Servier, Eisai Japan Laboratory.

Acknowledgements

I would like to thank Nick Barton for checking the text of the manuscript.

References (31)

  • S Lesage et al.

    Parkinson's disease: from monogenic forms to genetic susceptibility factors

    Hum Mol Genet

    (2009)
  • DT Dexter et al.

    Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease

    J Neurochem

    (1989)
  • ZI Alam et al.

    A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease

    J Neurochem

    (1997)
  • ZI Alam et al.

    Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra

    J Neurochem

    (1997)
  • EC Hirsch

    Why are nigral catecholaminergic neurons more vulnerable than other cells in Parkinson's disease?

    Ann Neurol

    (1992)
  • Cited by (32)

    • JWH133 inhibits MPP<sup>+</sup>-induced inflammatory response and iron influx in astrocytes

      2020, Neuroscience Letters
      Citation Excerpt :

      It is evident that iron accumulated in astrocytes in the SN of PD [18]. Divalent metal transporter-1 (DMT1), a proton-coupled metal-ion transport protein, can carry iron from the extracellular to the cytoplasm [19]. In cannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC)- treated cells, serine phosphorylation of DMT1 was significantly reduced [20].

    • Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease

      2019, Molecular and Cellular Neuroscience
      Citation Excerpt :

      Intriguingly, PD brain iron accumulation in the nigral area is in the form of neuromelanin adducts, which are detected by combined nigrosome-1 and neuromelanin-sensitive magnetic resonance imaging (NM-MRI), has emerged as a method for differential PD diagnosis (Jin et al., 2019; Medeiros et al., 2016). A reported increase in iron deposition is observed both in the nigral microglia and nigral DA neurons; however, given the fact that these results were obtained from the postmortem end-stage PD brains, it is plausible that phagocytized damaged dopaminergic neurons may be the source of iron deposits in microglia (Hirsch, 2009). Previous studies with MPTP-based experimental PD models elucidated the role of iron in exacerbating MPTP toxicity and the putative efficacy of iron chelators, such as lactoferrin, in neuroprotection against MPTP-induced DA neurodegeneration (Xu et al., 2019).

    • Mitochondrial ferritin suppresses MPTP-induced cell damage by regulating iron metabolism and attenuating oxidative stress

      2016, Brain Research
      Citation Excerpt :

      The results indicated that MPTP increased the iron level of the brain, and the significant upregulation of MtFt could exert protective effects against tissue damage caused by the MPTP-induced iron. The results above and those reported by others indicated that MPTP could cause the accumulation of iron in DA neurons in a PD model (Ayton et al., 2012; Faucheux et al., 1995; Hirsch, 2009). However, the role of MtFt is unclear in PD models induced by MPTP.

    View all citing articles on Scopus
    View full text