Midbrain iron content in early Parkinson disease

Martin, W. R. Wayne; Wieler, Marguerite; Gee, Myrlene

doi:10.1212/01.wnl.0000286384.31050.b5

Cited by 338 publications

(379 citation statements)

References 22 publications

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“…1,3 Also, the current finding that the caudal portion of the SN is more impaired than the rostral segment is consistent with recent proton density imaging techniques reflecting higher iron content caudally. 5 Other neuroimaging tests such as PET or SPECT distinguish patients with PD from healthy individuals. PET scans assessing [ 18 ]F-dopa uptake distinguished 100% of clinically moderate patients with PD from healthy controls, 20 with 85% correctly distinguished early in the disease.…”

Section: Resultsmentioning

confidence: 99%

“…Recent developments in neuroimaging techniques bring new promise for identifying surrogate markers of the degeneration within the SN in vivo. [4][5][6] Although diffusion tensor imaging (DTI) has typically been used to study white matter tracts, 7,8 it also holds promise for studying abnormalities in gray matter areas. As a method, DTI is based upon the diffusivity of water molecules, which exhibit a varying degree of tissue dependent anisotropy.…”

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confidence: 99%

“…Each patient with PD was prospectively matched with a corresponding control subject based on age and sex. Since previous studies suggest that the ventrolateral, caudal portion of the SN pars compacta manifests the greatest degeneration in PD, 3,5 we tested the hypothesis that the highest sensitivity and specificity for differentiating de novo PD from healthy individuals would be found in this area.…”

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confidence: 99%

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High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease

et al. 2009

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Section: Resultsmentioning

confidence: 99%

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High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease

et al. 2009

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“…Iron-Dopaminergic cell loss in the SNpc is reported to be accompanied by overaccumulation of unsequestered iron (22,23). To assess whether alterations in iron regulatory proteins as observed following DHB in our MPTP model coincide with any functional consequences, iron levels in the SN, striatum, and cerebellum were assessed in the various experimental conditions.…”

Section: Phd Inhibition By Dhb Prevents Mptp-induced Losses In Sn Levmentioning

confidence: 99%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target ␣ subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1␣ within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP ؉ -elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1␣ induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.Parkinson disease (PD) 2 is a neurodegenerative disorder primarily associated with loss of dopaminergic (DAergic) neurons of the pars compacta region of the substantia nigra (SNpc). Dopaminergic neurons are particularly prone to oxidative damage due to high levels of inherent reactive oxygen species that are produced during dopamine synthesis or its breakdown by monoamine oxidases or autoxidation to quinones (1-3). Importantly, iron bound to neuromelanin within DAergic neurons can subsequently react with metabolically liberated hydrogen peroxide through the Fenton reaction to produce extremely toxic hydroxyl radicals. If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life ...

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“…Iron accumulation has been found in the SN of PD patients and animal models [11][12][13][14][15][16][17][18][19] , and α-synuclein aggregation also exists in this area. The high concentration of ferric iron has been proved to promote the aggregation of A53T mutant α-synuclein in dopaminergic cells [20] .…”

Section: Introductionmentioning

confidence: 99%

Dose- and time-dependent α-synuclein aggregation induced by ferric iron in SK-N-SH cells

Jiang

Song

et al. 2010

Neurosci. Bull.

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Objective Intracellular formation of Lewy body (LB) is one of the hallmarks of Parkinson's disease. The main component of LB is aggregated α-synuclein, present in the substantia nigra where iron accumulation also occurs. The present study was aimed to study the relationship between iron and α-synuclein aggregation. Methods SK-N-SH cells were treated with different concentrations of ferric iron for 24 h or 48 h. MTT assay was conducted to determine the cell viability.Thioflavine S staining was used to detect α-synuclein aggregation. Results With the increase of iron concentration, the cell viability decreased significantly. At the concentrations of 5 mmol/L and 10 mmol/L, iron induced α-synuclein aggregation more severely than at the concentration of 1 mmol/L. Besides, 48-h treatment-induced aggregation was more severe than that induced by 24-h treatment, at the corresponding iron concentrations. Conclusion Ferric iron can induce α-synuclein aggregation, which is toxic to the cells, in a dose-and time-dependent way.

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Midbrain iron content in early Parkinson disease

Cited by 338 publications

References 22 publications

High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease

High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Dose- and time-dependent α-synuclein aggregation induced by ferric iron in SK-N-SH cells

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