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 New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Alessandra Bolotta ◽  
Provvidenza Maria Abruzzo ◽  
Vito Antonio Baldassarro ◽  
Alessandro Ghezzo ◽  
Katia Scotlandi ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cardiac Cells ◽  
Cardiac Differentiation ◽  
Specific Cell ◽  
Differentiation Markers ◽  
Cardiac Iron

Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich’s ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis.

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 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.

scholarly journals Molecular Analysis of Friedreich's Ataxia in Macedonian Patients

2008 ◽  
Vol 11 (1) ◽  
pp. 61-64 ◽  
Author(s):  
S Kocheva ◽  
S Trivodalieva ◽  
S Vlaski-Jekic ◽  
M Kuturec ◽  
G Efremov
Keyword(s):  
Molecular Analysis ◽  
Early Onset ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Autosomal Recessive Inheritance ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
The Republic ◽  
Gaa Repeats ◽  
Frataxin Gene

Molecular Analysis of Friedreich's Ataxia in Macedonian PatientsFriedreich's ataxia (FRDA) is rare a progressive neurodegenerative disorder of autosomal recessive inheritance, which is associated with an unstable expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. We have performed molecular analyses of the frataxin gene of 40 patients with spinocerebellar ataxia from the Republic of Macedonia. Fifteen had early onset of progressive ataxia (before the age of 25), while the remainder were over 25 years old at the time of diagnosis. Only 14 patients had a mutation in the frataxin gene and all of these had early onset ataxia. The number of GAA repeats was in the normal range in 50 healthy individuals.

scholarly journals Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1551
Author(s):  
Piergiorgio La Rosa ◽  
Sara Petrillo ◽  
Maria Teresa Fiorenza ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Cell Death ◽  
Neurodegenerative Disease ◽  
Neuronal Cell Death ◽  
Mitochondrial Protein ◽  
Neuronal Cell ◽  
Antioxidant Response ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Antioxidant Defenses ◽  
Special Focus

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

scholarly journals The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals

2010 ◽  
Vol 432 (1) ◽  
pp. 165-172 ◽  
Author(s):  
René Thierbach ◽  
Gunnar Drewes ◽  
Markus Fusser ◽  
Anja Voigt ◽  
Doreen Kuhlow ◽  
...  
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Disorder ◽  
Excision Repair ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Liver Tumours ◽  
Dna Repair Mechanisms ◽  
Dna Base ◽  
Repair Mechanisms ◽  
Base Excision

DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.

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.

scholarly journals Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

2001 ◽  
Vol 56 (5) ◽  
pp. 143-148 ◽  
Author(s):  
Lilian M. J. Albano ◽  
Mayana Zatz ◽  
A. Kim Chong ◽  
Débora Bertola ◽  
Sofia M. M. Sugayama ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Age At Onset ◽  
Cranial Nerves ◽  
Autosomal Recessive Inheritance ◽  
Molecular Study ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Expansion ◽  
Neurologic Findings

INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) - all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.

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