Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies
A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loa...
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Elsevier
2021-05-01
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Series: | Redox Biology |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721000446 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
L. Ma M. Gholam Azad M. Dharmasivam V. Richardson R.J. Quinn Y. Feng D.L. Pountney K.F. Tonissen G.D. Mellick I. Yanatori D.R. Richardson |
spellingShingle |
L. Ma M. Gholam Azad M. Dharmasivam V. Richardson R.J. Quinn Y. Feng D.L. Pountney K.F. Tonissen G.D. Mellick I. Yanatori D.R. Richardson Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies Redox Biology Neurodegeneration Parkinson's disease Iron |
author_facet |
L. Ma M. Gholam Azad M. Dharmasivam V. Richardson R.J. Quinn Y. Feng D.L. Pountney K.F. Tonissen G.D. Mellick I. Yanatori D.R. Richardson |
author_sort |
L. Ma |
title |
Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies |
title_short |
Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies |
title_full |
Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies |
title_fullStr |
Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies |
title_full_unstemmed |
Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies |
title_sort |
parkinson's disease: alterations in iron and redox biology as a key to unlock therapeutic strategies |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2021-05-01 |
description |
A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The “gold standard” histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca+2 channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected. |
topic |
Neurodegeneration Parkinson's disease Iron |
url |
http://www.sciencedirect.com/science/article/pii/S2213231721000446 |
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doaj-ec89f3f76aee4972a05b3b33c7cae7512021-05-02T05:54:20ZengElsevierRedox Biology2213-23172021-05-0141101896Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategiesL. Ma0M. Gholam Azad1M. Dharmasivam2V. Richardson3R.J. Quinn4Y. Feng5D.L. Pountney6K.F. Tonissen7G.D. Mellick8I. Yanatori9D.R. Richardson10School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaSchool of Medical Science, Griffith University, Gold Coast, Queensland, AustraliaSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, AustraliaDepartment of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, JapanSchool of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Corresponding author. Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia.A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The “gold standard” histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca+2 channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected.http://www.sciencedirect.com/science/article/pii/S2213231721000446NeurodegenerationParkinson's diseaseIron |