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dc.contributor.authorMa, L
dc.contributor.authorGholam.Azad, M
dc.contributor.authorDharmasivam, M
dc.contributor.authorRichardson, V
dc.contributor.authorQuinn, RJ
dc.contributor.authorFeng, Y
dc.contributor.authorPountney, DL
dc.contributor.authorTonissen, KF
dc.contributor.authorMellick, GD
dc.contributor.authorYanatori, I
dc.contributor.authorRichardson, DR
dc.date.accessioned2021-03-31T04:38:04Z
dc.date.available2021-03-31T04:38:04Z
dc.date.issued2021
dc.identifier.issn2213-2317
dc.identifier.doi10.1016/j.redox.2021.101896
dc.identifier.urihttp://hdl.handle.net/10072/403529
dc.description.abstractA 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.
dc.description.peerreviewedYes
dc.languageen
dc.publisherElsevier BV
dc.relation.ispartofpagefrom101896
dc.relation.ispartofjournalRedox Biology
dc.relation.ispartofvolume41
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchMedical biochemistry and metabolomics
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3205
dc.subject.fieldofresearchcode3214
dc.titleParkinson’s Disease: Alterations in Iron and Redox Biology as a Key to Unlock Therapeutic Strategies
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMa, L; Gholam.Azad, M; Dharmasivam, M; Richardson, V; Quinn, RJ; Feng, Y; Pountney, DL; Tonissen, KF; Mellick, GD; Yanatori, I; Richardson, DR, Parkinson’s Disease: Alterations in Iron and Redox Biology as a Key to Unlock Therapeutic Strategies, Redox Biology, 2021, 41, pp. 101896
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated2021-03-03T05:21:37Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorFeng, Yun J.
gro.griffith.authorTonissen, Kathryn F.
gro.griffith.authorPountney, Dean L.
gro.griffith.authorMellick, George
gro.griffith.authorQuinn, Ronald J.
gro.griffith.authorMa, Linlin
gro.griffith.authorRichardson, Des R.
gro.griffith.authorDharmasivam, Mahendiran
gro.griffith.authorRichardson, Vera
gro.griffith.authorGholam Azad, Mahan


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