scholarly journals Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs

2019 ◽  
Vol 20 (20) ◽  
pp. 5211 ◽  
Author(s):  
Sara Petrillo ◽  
Jessica D’Amico ◽  
Piergiorgio La Rosa ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Dimethyl Fumarate ◽  
Friedreich’S Ataxia ◽  
Nerve Fibers ◽  
Friedreich's Ataxia ◽  
Related Factor ◽  
Iron Sulfur Cluster ◽  
Redox Active ◽  
Nrf2 Activation ◽  
Clinical Benefits ◽  
Skin Biopsies

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich’s Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.

Deciphering Mitochondrial Iron Metabolism Using a Knockout Mouse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1995-1995
Author(s):  
Michael Huang ◽  
Erika Becker ◽  
Megan Whitnall ◽  
Yohan Suryo Rahmanto ◽  
Prem Ponka ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Uptake ◽  
Knockout Mouse ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Down Regulation ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract 1995 Poster Board I-1017 We utilized the muscle creatine kinase conditional frataxin knockout mouse to elucidate how frataxin-deficiency alters iron metabolism. This is of significance since frataxin-deficiency leads to the neuro- and cardio-degenerative disease, Friedreich's ataxia. Using cardiac tissues, we demonstrate that frataxin-deficiency leads to down-regulation of key molecules involved in three mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase, Nfs1); mitochondrial-iron storage (mitochondrial ferritin); and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase and ferrochelatase). This marked decrease in mitochondrial-iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excess mitochondrial-iron observed. Indeed, this effect is compounded by increased iron availability for mitochondrial uptake through: (1) transferrin receptor1 up-regulation that increases iron uptake from transferrin; (2) decreased ferroportin1 expression, limiting iron export; (3) increased expression of the heme catabolism enzyme, heme oxygenase1, and down-regulation of ferritin-H and —L, both of which likely lead to increased “free iron” for mitochondrial uptake; and (4) increased expression of the mammalian exocyst protein, Sec15l1, and the mitochondrial-iron importer, mitoferrin-2 (Mfrn2), that facilitate cellular iron uptake and mitochondrial-iron influx, respectively. This study enables construction of a model explaining the cytosolic iron-deficiency and mitochondrial-iron-loading in the absence of frataxin that is important for understanding the pathogenesis of Friedreich's ataxia. Disclosures: No relevant conflicts of interest to declare.

Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich's ataxia fibroblasts

Blood ◽  
2021 ◽  
Author(s):  
Floriane Petit ◽  
Anthony Drecourt ◽  
Michaël Dussiot ◽  
Coralie Zangarelli ◽  
Olivier Hermine ◽  
...  
Keyword(s):  
Iron Overload ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gene Encoding ◽  
Iron Sulfur Cluster ◽  
The Road ◽  
Cellular Iron

Friedreich's ataxia (FRDA) is a frequent autosomal recessive disease caused by a GAA repeat expansion in the FXN gene encoding frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Resulting frataxin deficiency affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed transferrin recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, we demonstrate that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.

scholarly journals Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0217776 ◽  
Author(s):  
Mittal Jasoliya ◽  
Francesco Sacca ◽  
Sunil Sahdeo ◽  
Frederic Chedin ◽  
Chiara Pane ◽  
...  
Keyword(s):  
Dimethyl Fumarate ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia

scholarly journals The Neuropathy of Charlevoix-Saguenay Ataxia: An Electrophysiological and Pathological Study

1979 ◽  
Vol 6 (2) ◽  
pp. 199-203 ◽  
Author(s):  
J.M. Peyronnard ◽  
L. Charron ◽  
A. Barbeau
Keyword(s):  
Action Potentials ◽  
Friedreich’S Ataxia ◽  
Nerve Fibers ◽  
Friedreich's Ataxia ◽  
Myelinated Fiber ◽  
Fiber Density ◽  
Primary Defect ◽  
Internodal Length ◽  
Sensory Action ◽  
Upper And Lower Extremities

SummaryTwo female patients aged 30 and 40 years with the Charlevoix-Saguenay ataxia were studied. Both had absent sensory action potentials in upper and lower extremities but, unlike typical cases of Friedreich's ataxia, they displayed a marked slowing of motor conduction velocities. Sural nerve biopsies taken from calf and ankle revealed a severe loss of large my elina ted axons contrasting with a normal myelinated fiber density. Evidence for active axonal degeneration was scarce, with no indication of axonal regeneration.Teased myelinated fibers revealed an increased variability of internodal length but no evidence for myelin breakdown. These findings support, as a primary defect, a developmental abnormality of peripheral nerve, namely a lack of maturation of large myelinated axons and possibly a faulty myelination of nerve fibers. We think it is unlikely to represent a progressive axonal atrophie or dystrophic process, as suggested in Friedreich's ataxia.

Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia

2016 ◽  
Vol 130 (11) ◽  
pp. 853-870 ◽  
Author(s):  
Shannon Chiang ◽  
Zaklina Kovacevic ◽  
Sumit Sahni ◽  
Darius J.R. Lane ◽  
Angelica M. Merlot ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Antioxidant Defense ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Iron Loading ◽  
Iron Sulfur Cluster ◽  
Cell Vitality ◽  
Mitochondrial Iron

The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron–sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.

scholarly journals Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Liwei Weng ◽  
Laurent Laboureur ◽  
Qingqing Wang ◽  
Lili Guo ◽  
Peining Xu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mouse Models ◽  
Human Subjects ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Mouse Heart ◽  
Mitochondrial Enzymes ◽  
Iron Sulfur Cluster ◽  
Mouse Tissues ◽  
Mature Mouse

Abstract Mature frataxin is essential for the assembly of iron–sulfur cluster proteins including a number of mitochondrial enzymes. Reduced levels of mature frataxin (81-20) in human subjects caused by the genetic disease Friedreich’s ataxia results in decreased mitochondrial function, neurodegeneration, and cardiomyopathy. Numerous studies of mitochondrial dysfunction have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, we have discovered that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

scholarly journals The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

2020 ◽  
Vol 21 (3) ◽  
pp. 916 ◽  
Author(s):  
Piergiorgio La Rosa ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Cellular Response ◽  
Iron Homeostasis ◽  
Nuclear Translocation ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Signaling Network ◽  
Related Factor ◽  
Clinical Biomarkers

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

scholarly journals Neurodegeneration in Friedreich’s Ataxia: From Defective Frataxin to Oxidative Stress

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Cláudio M. Gomes ◽  
Renata Santos
Keyword(s):  
Oxidative Stress ◽  
Iron Homeostasis ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Missense Mutations ◽  
Coding Region ◽  
Iron Sulfur Cluster ◽  
Central Nervous Systems ◽  
And Function

Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of theFXNgene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with anα/βsandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in theFXNcoding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.

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