Assessment of cell-free levels of iron and copper in patients with Friedreich’s ataxia

Pathak, Deepti; Srivastava, Achal Kumar; Gulati, Sheffali; Rajeswari, Moganty R.

doi:10.1007/s10534-019-00186-4

Cited by 9 publications

(9 citation statements)

References 52 publications

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“…Previous findings have highlighted iron metabolism dysregulation in heart autopsies of FRDA patients 18,19 . Moreover, iron concentrations in plasma samples were found to be significantly lower in FRDA patients compared to healthy controls 20 . These observations align cohesively with our results, further emphasizing the potential role of Slc40a1 in the pathological mechanisms underlying FRDA.…”

Section: Biomarkers In Frdakd Mouse Modelmentioning

confidence: 90%

Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia

Koka,

Li,

Akther

et al. 2023

Preprint

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Friedreich's Ataxia (FRDA) is a neurodegenerative disorder caused by reduced frataxin (FXN) levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia with no cure, FRDA lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study identifies long non-coding RNA Tug1 as a potential blood-based FRDA biomarker. In a previous study using a frataxin knockdown mouse model (FRDAkd), we observed several hallmark FRDA symptoms and abnormalities in various tissues. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from FRDA patients with tissue samples from affected areas in FRDAkd mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of FRDA patients, carriers, and controls, as well as 192 tissue datasets from FRDAkd mice. Blood and tissue samples underwent RNA isolation and qRT-PCR, and frataxin knockdown was confirmed through ELISA. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum and blood samples on an independent set of 45 healthy controls, 45 FRDA patients; 66 heterozygous carriers, and 72 FRDA patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the FRDAkd mouse model (One-way ANOVA, p ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R2 = 0.71 during depletion, R2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1's downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of FRDA patients compared to controls (Wilcoxon signed-rank test, p < 0.05). Regression analyses revealed a negative correlation between TUG1 levels and disease onset (p < 0.0037), and positive correlations with disease duration and Functional Disability Stage score (p < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. In summary, this study highlights Tug1 as a crucial blood-based biomarker for FRDA. Tug1's consistent expression variance across human and mouse tissues is closely associated to disease severity and key FRDA pathways. It also correlates strongly with Fxn levels, making it a promising early, non-invasive marker. TUG1 offers potential for FRDA monitoring and therapeutic development, warranting further clinical research.

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Section: Biomarkers In Frdakd Mouse Modelmentioning

confidence: 90%

Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia

Koka,

Li,

Akther

et al. 2023

Preprint

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“…Fe-positive granules in cardiomyocytes ↓ serum Fe [90][91][92][93] ↑ Fe in dentate nucleus, red nucleus [94,95] Fe switched from oligodendroglia to microglia in dentate nucleus [96][97][98] Fe presumably primarily accumulated in mitochondria [99,100] Wilson Disease ↑ Fe in liver ↑ serum Fe, ferritin, hepcidin, soluble transferrin receptor [101][102][103] ↑ Fe in globus pallidus, putamen, caudate, thalamus, substantia nigra, red nucleus, subthalamic nucleus [104,105] ↑ Fe in excessive macrophages, astrocytes [106] n.a.…”

Section: Friedreich Ataxiamentioning

confidence: 99%

“…On the other hand, plasma Fe was found to be decreased in FRDA compared to controls. This may be theoretically explained by upregulation of intracellular Fe uptake that leads to extracellular Fe deficiency [93].…”

Section: Other Genetic Disorders With Brain Iron Depositsmentioning

confidence: 99%

Cerebral Iron Deposition in Neurodegeneration

et al. 2022

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Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

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“…Increased levels of circulating transferrin receptor (TfR) found in FRDA patient blood plasma levels reflect depletion of intracellular iron (Wilson et al, 2000). FRDA patients exhibit decreased blood plasma-iron levels and cytosolic ferritin levels shifted to higher concentration of its light-chain than heavy-chain counterparts in the dentate nucleus, indicating iron transport from the circulation but bypass of cytosolic storage (Koeppen et al, 2007;Pathak et al, 2019). Furthermore, FRDA patient heart, liver, and spleen sections analyzed for iron content using Perl's stain demonstrate extra-nuclear iron deposition, and in a chain-like organization, indicating mitochondrial localization (Bradley et al, 2000).…”

Section: The Foundation Of Frda Pathologymentioning

confidence: 99%

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

Smith

Kosman

2020

Front. Mol. Biosci.

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Friedreich’s ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory–motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial chaperone protein required for incorporation of iron into iron–sulfur cluster and heme precursors. After the discovery of the molecular basis of FRDA in 1996, over two decades of research have been dedicated to understanding the temporal manifestations of disease both at the whole body and molecular level. Early research indicated strong cellular iron dysregulation in both human and yeast models followed by onset of oxidative stress. Since then, the pathophysiology due to dysregulation of intracellular iron chaperoning has become central in FRDA relative to antioxidant defense and run-down in energy metabolism. At the same time, limited consideration has been given to changes in cytoskeletal organization, which was one of the first molecular defects noted. These alterations include both post-translational oxidative glutathionylation of actin monomers and differential DNA processing of a cytoskeletal regulator PIP5K1β. Currently unknown in respect to FRDA but well understood in the context of FXN-deficient cell physiology is the resulting impact on the cytoskeleton; this disassembly of actin filaments has a particularly profound effect on cell–cell junctions characteristic of barrier cells. With respect to a neurodegenerative disorder such as FRDA, this cytoskeletal and tight junction breakdown in the brain microvascular endothelial cells of the blood–brain barrier is likely a component of disease etiology. This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.

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Assessment of cell-free levels of iron and copper in patients with Friedreich’s ataxia

Cited by 9 publications

References 52 publications

Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia

Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia

Cerebral Iron Deposition in Neurodegeneration

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

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