Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism

Dekker, Marieke; Giesbergen, P. C.L.M.; Njajou, Omer T.; Swieten, John van; Hofman, Albert; Breteler, Monique M.B.; Duijn, Cornelia M. van

doi:10.1016/s0304-3940(03)00713-4

Cited by 83 publications

(55 citation statements)

References 18 publications

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“…It is accepted that a chronic insufficiency of venous drainage leads to increased iron stores in the affected tissue [9,26]. Several studies investigated the relationship between iron overload and neurodegenerative disease such as Alzheimer disease, Parkinson disease, and other disorders [27][28][29][30]. However, differently from the above reported diseases, in which the increased iron stores are not related to impaired venous function, our study demonstrates a strong association between MS and anomalies of cerebral venous drainage.…”

Section: Discussioncontrasting

confidence: 56%

“…Had Doppler hemodynamic anomalies been present in the healthy aged control group, we would not have been able to maintain that they have a role in MS, since these subjects are older than the median age of onset of MS [23]. Therefore, the absence of Doppler venous outflow abnormalities in the OND patients would indicate that in no other disease of the nervous system can this mechanism play a role, neither in other pathologies that, like MS, present neurodegenerative, neuroimmunitary, and neurovascular aspects, nor iron deposition as epiphenomenon [26][27][28][29][30][31].…”

Section: Discussionmentioning

confidence: 94%

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The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis

Zamboni

Menegatti

Galeotti

et al. 2009

Journal of the Neurological Sciences

199

367

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 94%

The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis

Zamboni

Menegatti

Galeotti

et al. 2009

Journal of the Neurological Sciences

199

367

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“…This proposed neuropathological pathway would depend upon the redox state of the iron stores and possibly their subcellular compartmentation. A recent association between HH and subsequent Parkinsonism has recently been reported (Dekker et al, 2003;Costello et al, 2004).…”

Section: Effects Of Increased Iron Levels On Th Activity and Hemochromentioning

confidence: 99%

Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis

Kaushik¹,

Gorin

Vali³

2006

J Comput Neurosci

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Tyrosine hydroxylase's catalysis of tyrosine to dihydroxyphenylalanine (DOPA) is the highly regulated, rate-limiting step catalyzing the synthesis of the catecholamine neurotransmitter dopamine. Phosphorylation, cofactor-mediated regulation, and the cell's redox status, have been shown to regulate the enzyme's activity. This paper incorporates these regulatory mechanisms into an integrated dynamic model that is capable of demonstrating relative rates of dopamine synthesis under various physiological conditions. Most of the kinetic equations and substrate parameters used in the model correspond with published experimental data, while a few which were not available in literature have been optimized based on explicit assumptions. This kinetic pathway model permits a comparison of the relative regulatory contributions made by variations in substrate, phosphorylation, and redox status on enzymatic activity and permits predictions of potential disease states. For example, the model correctly predicts the recent observation that individuals with haemochromatosis and having excessive iron accumulation are at increased risk for acquiring Parkinsonism, a defect in neuronal dopamine synthesis (Bartzokis et al., 2004; Costello et al., 2004). Alpha synuclein mediated regulation of tyrosine hydroxylase has also been incorporated in the model, allowing an insight into the overexpression and aggregation of alpha synuclein in Parkinson's disease.

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“…Iron overload has been postulated to play a role in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease [12], Alzheimer's disease [13,14], and amyotrophic lateral sclerosis [15]. This suggests that the central nervous system is susceptible to iron-induced oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

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SummaryHepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells, and retinal pigment epithelium (RPE) within the retina. Since the retina is protected by the retinal-blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells, and RPE, closely resembling the expression pattern of ferroportin. We also show that bacterial lipopolysaccharide (LPS) is a regulator of hepcidin expression in Müller cells and RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the Toll-like receptor-4. The upregulation of hepcidin by LPS occurs independent of Hfe (Human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent downregulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

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Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism

Cited by 83 publications

References 18 publications

The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis

The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis

Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

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