Increased Ndfip1 in the Substantia Nigra of Parkinsonian Brains Is Associated with Elevated Iron Levels

Howitt, Jason; Gysbers, Amanda; Ayton, Scott; Carew‐Jones, Francine; Putz, Ulrich; Finkelstein, David I.; Halliday, Glenda M.; Tan, Seong‐Seng

doi:10.1371/journal.pone.0087119

Cited by 30 publications

(30 citation statements)

References 33 publications

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“…The chronic treatment with iron can increase the expression of Ndfip 1 in MES23.5 cells, 16 but Ndfip1 is not expressed in glial cells. 17 Our results also support that Ndfip1 rarely existed in glial cells with or without iron treatment.…”

Section: Discussionsupporting

confidence: 83%

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

Xia¹,

Liang²,

Li³

et al. 2020

Preprint

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Metal implants are used worldwide, with millions of metal nails, plates and fixtures grafted during orthopaedic surgeries. Iron is the most common element of these metal implants. As time passes metal elements can be corroded and iron can be released from the implants in the form of ferric (Fe 3+ ) or ferrous (Fe 2+ ). These iron ions can permeate the surrounding tissues and enter circulation; importantly both Fe 3+ and Fe 2+ freely pass blood brain barrier (BBB). Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that the probability of metal implants delivered through orthopaedic surgeries was higher in patients of Parkinson's diseases (PD) or ischemic stroke than in healthy subjects. This finding instigated subsequent study of iron effects on neuronal cells. In experiments in vivo, we found that iron selectively decreased presence of divalent metal transporter 1 (DMT1) in neurones through increasing the expression of Ndfip1, which degrades DMT1 and rarely exists in glial cells. At the same time iron accumulation increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microglial activation. Facing the attack of excess iron, glial cells act as neuroprotectors to uptake more extracellular iron by up-regulating DMT1, whereas neurones limit iron uptake through decreasing DMT1 operation. Cerebral accumulation of iron was associated with impaired cognition, locomotion and mood. Excess iron thus affects neural cells and could increase the risk of neurodegeneration.

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Section: Discussionsupporting

confidence: 83%

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

Xia¹,

Liang²,

Li³

et al. 2020

Preprint

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“…Interestingly, ceruloplasmin, a protein acting as an iron export ferroxidase, showed decreased activity in the SN (Howitt et al . ).…”

Section: Transition Metals Calcium and Calcium‐binding Proteinsmentioning

confidence: 97%

“…Increased iron has been linked to other pathogenetically relevant features of PD, including oxidative stress and mitochondrial function . Moreover, several proteins that bind to or transport iron are also deregulated: the expression of such iron transport machinery like divalent metal transporter 1 (Salazar et al 2008), transferrin (Mastroberardino et al 2009), Nedd4 family interacting protein 1 (Howitt et al 2014), a protein implicated in the posttranslational control of divalent metal transporter 1, the iron export protein ferroportin (Visanji et al 2013), as well as the iron-binding proteins ferritin (Riederer et al 1989), lactoferrin (Leveugle et al 1996;Rousseau et al 2013) and its receptor are all increased in the SN of PD patients. Interestingly, ceruloplasmin, a protein acting as an iron export ferroxidase, showed decreased activity in the SN (Howitt et al 2014).…”

Section: Transition Metals Calcium and Calcium-binding Proteinsmentioning

confidence: 99%

Molecular changes in the postmortem parkinsonian brain

Toulorge

Schapira²,

Hajj

2016

Journal of Neurochemistry

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Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by 'reverse biochemistry' i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD.

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“…It binds to Hect family proteins such as Nedd4 in the WW-PY manner through the PY motif (Ferreira et al, 2011;Wang et al, 2012;Howitt et al, 2014;Martínez-Pacheco et al, 2014). The presence of PY motifs in Ndfipl has a direct relationship with its functions, and the use of the dominant-negative mutant (mutation of two PY motifs) of Ndfipl has contributed to research elucidating its functions and mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

Protective effects and mechanisms of Ndfipl on SH-SY5Y cell apoptosis in an in vitro Parkinson’s disease model

Li¹,

Guo²,

Wang³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of the current study was to examine the protective effects and mechanisms of Ndfipl on neurocytes in an experimental in vitro Parkinson's disease model induced by MPP We further studied the roles of Ndfipl in inhibiting MPP + -induced SH-SY5Y apoptosis, protection, and ubiquitination of SH-SY5Y cells. Our results showed that Ndfipl reduced apoptosis and improved cell survival rate, indicating that Ndfipl has a neuroprotective effect. Furthermore, we found that Ndfipl binds to Nedd4-1, and that increased expression of Ndfipl significantly reduced Itch expression. We also found that increased ubiquitination played a role in Ndfipl-mediated processes, and that Ndfipl and α-synuclein interact. Additionally, the expression of Ndfipl reduced expression of α-synuclein. In conclusion, Ndfipl plays a significant role in protecting SH-SY5Y cells in in vitro Parkinson's disease models.

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Increased Ndfip1 in the Substantia Nigra of Parkinsonian Brains Is Associated with Elevated Iron Levels

Cited by 30 publications

References 33 publications

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

Molecular changes in the postmortem parkinsonian brain

Protective effects and mechanisms of Ndfipl on SH-SY5Y cell apoptosis in an in vitro Parkinson’s disease model

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