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Iron Neurotoxicity in Parkinson’s Disease

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Handbook of Neurotoxicity

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Abstract

Iron plays essential roles in the early development of cognitive processes and in the maintenance of neuronal functions in the mature brain; therefore, neurons have expeditious mechanisms to ensure a readily available iron supply. However, several neurodegenerative diseases present dysregulation of iron homeostasis derived from mitochondrial dysfunction, inflammatory conditions, decreased glutathione levels, and oxidative damage, resulting in downstream protein aggregation, lipid peroxidation, and nucleic acid modification. In this chapter, the mechanisms by which iron homeostasis is lost in Parkinson’s disease (PD) are discussed. The relevance of endogenous toxins such as mediators of mitochondrial dysfunction, the relationship between inflammation and iron dyshomeostasis, and the role of hepcidin as a neuroprotective agent are also addressed. A model is proposed that involves a positive feedback loop between mitochondrial dysfunction, inflammation, and increased iron content in dopaminergic neurons, which, if unchecked, ends in substantia nigra (SN) neuronal death.

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Abbreviations

6-OHDA:

6-hydroxydopamine

AD:

Alzheimer’s disease

ALAS2:

5′-aminolevulinate synthase 2

APP:

Amyloid precursor protein

ARE:

Antioxidant response element

ATP13A2:

ATPase cation transporting 13A2

Aβ:

Amyloid β

CDC14A:

Dual specificity protein phosphatase

CDKAL1:

CDK5 Regulatory Subunit Associated Protein 1 Like 1

CNS:

Central nervous system

CP:

Ceruloplasmin

CSF:

Cerebrospinal fluid

Dexras1:

Dexamethasone-induced Ras protein 1

DJ-1:

PARK7, Parkinson disease protein 7

DMT1:

SLC11A2, divalent metal transporter 1

Erv1:

Mitochondrial FAD-linked sulfhydryl oxidase ERV1

FBXL5:

F-Box and Leucine-Rich Repeat Protein 5

Fe-S:

Iron-sulfur

FPN1:

SCL40A, ferroportin 1

GPX4:

Glutathione peroxidase 4

HIF:

Hypoxia inducible factor

HRE:

HIF response element

IFNγ:

Interferon gamma

IL:

Interleukin

IRE:

Iron responsive element

IRP:

Iron regulatory protein

KIF4A:

Kinesin Family Member 4A

L-DOPA:

l-3,4-dihydroxyphenylalanine

LIMK1:

LIM domain kinase 1

LIP:

Labile iron pool

LPS:

Lipopolysaccharide

LRRK2:

Leucine-rich repeat kinase 2

L-VGCC:

L-type voltage-gated calcium channel

MPP+:

1-methyl-4-phenylpyridinium

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MRCKα:

Myotonic dystrophy kinase-related Cdc42-binding kinase α

NDUFS4:

NADH-ubiquinone oxidoreductase subunit S4

NFκB:

Nuclear factor kappa B

Nfs1: NMDA:

N-Methyl-d-aspartate

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

Nrf2:

Nuclear factor erythroid 2-related factor 2

NTBI:

Non-transferring bound iron

ONOO−:

Peroxynitrite

PAP7:

PKA-associated protein 7

PD:

Parkinson’s disease

PINK-1:

PTEN-induced putative kinase 1

PSP-PDC:

Progressive supranuclear palsy, parkinsonism-dementia complex

PUFAs:

Polyunsaturated fatty acids

RBC:

Red blood cells

ROS:

Reactive oxygen species

SN:

Substantia nigra

Steap:

Six-transmembrane epithelial antigen of the prostate

Tf:

Transferrin

TfR1:

Transferrin receptor 1

TLR4:

Toll-like receptor 4

TNF:

Tumor necrosis factor

UPDRS:

Unified Parkinson’s Disease Rating Scale

UTR:

Untranslated region

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Acknowledgments

This research was funded by the FONDECYT Initiation in Research, grant number 11201141, awarded to P.J.U.

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Authors and Affiliations

  1. Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile

    Pamela J. Urrutia & Marco T. Núñez

  2. Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, Santiago, Chile

    Daniel Bórquez

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  1. Pamela J. Urrutia
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  2. Daniel Bórquez
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  3. Marco T. Núñez
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Correspondence to Marco T. Núñez .

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Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Urrutia, P.J., Bórquez, D., Núñez, M.T. (2021). Iron Neurotoxicity in Parkinson’s Disease. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_11-1

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  • DOI: https://doi.org/10.1007/978-3-030-71519-9_11-1

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