Decreased transferrin receptor expression by Neuromelanin cells in restless legs syndrome
Abstract
BACKGROUND: Restless legs syndrome (RLS) is a sensory-movement disorder affecting 5 to 10% of the population. Its etiology is unknown, but MRI analyses and immunohistochemical studies on autopsy tissue suggest the substantia nigra (SN) of patients with RLS has subnormal amounts of iron. METHODS: Neuromelanin cells from the SN of four RLS and four control brains were isolated by laser capture microdissection, and a profile of iron-management protein expression was obtained by immunoblot analysis. Binding assays for iron regulatory protein activity were performed on cell homogenates. RESULTS: Ferritin, divalent metal transporter 1, ferroportin, and transferrin receptor (TfR) were decreased in RLS neuromelanin cells compared with control. Transferrin was increased in RLS neuromelanin cells. This protein profile in RLS neuromelanin cells is consistent with iron deficiency with the exception that TfR expression was decreased rather than increased. The concentration and activity of the iron regulatory proteins (IRP1 and IRP2) were analyzed to determine whether there was a functional deficit in the post-transcriptional regulatory mechanism for TfR expression. Total IRP activity, IRP1 activity, and IRP1 protein levels were decreased in RLS, but total IRP2 protein levels were not decreased in RLS. CONCLUSION: Restless legs syndrome may result from a defect in iron regulatory protein 1 in neuromelanin cells that promotes destabilization of the transferrin receptor mRNA, leading to cellular iron deficiency.
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Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.
“Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.198–200”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [200]
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The role of iron in brain ageing and neurodegenerative disorders
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- Authors
- Connor, J. R., Wang, X. S., Patton, S. M., Menzies, S. L., Troncoso, J. C., Earley, C. J., & Allen, R. P.
- Affiliations
- Pennsylvania State University (US)
- Venue
- Neurology
- Published
- 2004-05-11
- Volume
- 62
- Issue
- 9
- Pages
- 1563-1567
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2060362040
- Cited by
- 199
- References
- 36
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 4 · 2015: 12 · 2014: 10 · 2013: 9 · 2012: 9
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Restless Legs Syndrome Foundation
- National Institute on Aging (P50AG005146, AG 05146)
- National Institute of Neurological Disorders and Stroke (R01NS042857, P50NS38377, P50NS038377, NS042857)
- Topics
- Health Sciences › Medicine › Epidemiology › Restless Legs Syndrome Research
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- restless legs syndrome, substantia nigra, transferrin receptor, iron regulatory protein 1, IRP2, iron deficiency, iron metabolism, ferritin, DMT1, ferroportin, transferrin, post-transcriptional regulation, mRNA stability
- MeSH terms
- Aged, Aged, 80 and over, Female, Humans, Iron, Male, Melanins, Middle Aged, Nerve Tissue Proteins, Neurons, Receptors, Transferrin, Restless Legs Syndrome, RNA, Messenger, Substantia Nigra, Transferrin, Gene Expression, In Situ Hybridization, Anemia, Iron-Deficiency, Iron-Regulatory Proteins, Microdissection
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