New Progress on the Role of Glia in Iron Metabolism and Iron-Induced Degeneration of Dopamine Neurons in Parkinson's Disease

Abstract

It is now increasingly appreciated that glial cells play a critical role in the regulation of iron homeostasis. Impairment of these properties might lead to dysfunction of iron metabolism and neurodegeneration of neurons. We have previously shown that dysfunction of glia could cause iron deposit and enhance iron-induced degeneration of dopamine (DA) neurons in Parkinson's disease (PD). There also has been a substantial growth of knowledge regarding the iron metabolism of glia and their effects on iron accumulation and degeneration of DA neurons in PD in recent years. Here, we attempt to describe the role of iron metabolism of glia and the effect of glia on iron accumulation and degeneration of DA neurons in the substantia nigra of PD. This could provide evidence to reveal the mechanisms underlying nigral iron accumulation of DA neurons in PD and provide the basis for discovering new potential therapeutic targets for PD.

Keywords: Parkinson’s disease; dopamine neurons; glia; iron; iron transporters.

FIGURE 1

Abnormal expression of iron transporters caused iron accumulation in DA neurons in PD. Neurotoxin induced up-regulation of iron importer DMT1 and down-regulation of iron export protein FPN1 in PD via activation of IRPs. This abnormal expression of iron transporters caused iron accumulation and enhanced iron-induced neurotoxicity in dopaminergic neurons in PD.

FIGURE 2

Schematic illustration of brain iron metabolism. Iron could cross BBB though endocytosis of holo-Tf followed by iron detached from Tf inside endosomes and FPN1-mediated iron efflux or transcytosis of holo-Tf through the BVECs. (1) Astrocyte: astrocytes could uptake Fe³⁺ via Tf-TfR1. DMT1, Zip14, and TRPC participate in Fe²⁺ absorption. Cp can oxidize Fe²⁺ to Fe³⁺ and then promote FPN1-mediated Fe²⁺ release. Iron can be stored in ferritin efficiently. (2) Microglia: Fe²⁺ could be transported via DMT1-mediated iron import and FPN1-mediated iron export. Microglia also can transfer Fe³⁺ ions to neurons by Lf/LfR-mediated pathway and store iron in ferritin. (3) Oligodendrocytes: iron is stored in oligodendrocytes mainly in the form of ferritin or Tf. Tf could be released from oligodendrocytes. Tim2-induced ferritin uptake is considered as the main mechanism for iron intake. Ferritin released from astrocyte and microglia promotes OPC maturation. BBB, blood–brain barrier; BVECs, brain capillary endothelial cells; Cp, ceruloplasmin; FPN1, ferroportin1; Lf/LfR, lactoferrin/lactoferrin receptor; NTBI, non-transferrin-bound iron; OPC, oligodendrocyte precursor cell; Tf/TfR1, transferrin/transferrin receptor 1; TRPC, resident transient receptor potential channel; Zip14, Zrt/Irt-like protein 14.

FIGURE 3

Schematic illustration showing several effects of microglia on iron metabolism and degeneration of DA neurons in PD. (1) Iron overload-induced activation of microglia increases the release of Lf, which provides neuroprotection against MPP⁺ in DA neurons. (2) LPS could induce the release of IL-6 in microglia, which could increase the expression of hepcidin in DA neurons, thus inhibiting FPN1-mediated iron efflux in DA neurons. (3) Excessive activation of microglia induced by LPS or neurotoxins could release IL-1β and TNF-α, which aggravates iron accumulation of DA neurons by up-regulating DMT1+IRE and down-regulating FPN1. (4) MMP-9 released by damaged DA neurons could lead to upregulation and release of LCN2. LCN2 then activates microglia to release TNF-α and IL-1β, which is involved in the abnormal expression of DMT1 and FPN1 in DA neurons. LCN2 released from activated microglia might also induce direct neurotoxicity via excessive iron delivery into DA neurons by binding to LCN2 receptors.

FIGURE 4

Schematic illustration showing the effects of astrocytes on iron accumulation in dopaminergic neurons in PD. (1) IL-6 could promote astrocytes to release hepcidin, which then prevents FPN1-mediated iron release from DA neurons. (2) BDNF and GDNF secreted by activated astrocytes can inhibit IRP via acting on their receptors, thus down-regulating the expression of DMT1 and reducing iron accumulation in DA neurons. (3) MMP-9 released by damaged DA neurons could lead to upregulation and release of LCN2. LCN2 then activates astrocytes to release TNF-α and IL-1β, which up-regulates DMT1 and down-regulates FPN1 in DA neurons. Released LCN2 might also induce direct neurotoxicity via excessive iron delivery into DA neurons by binding to LCN2 receptors.