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Frataxin

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https://www.readbyqxmd.com/read/29898895/identification-of-cardioprotective-drugs-by-medium-scale-in-vivo-pharmacological-screening-on-a-drosophila-cardiac-model-of-friedreich-s-ataxia
#1
Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier
Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions...
June 13, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29878710/oligonucleotides-hold-promise-as-a-therapy-for-friedreich-s-ataxia-friedreich-s-ataxia-currently-is-incurable-but-synthetic-antisense-oligonucleotides-have-demonstrated-promising-results-in-increasing-frataxin-gene-expression-and-restoring-it-to-normal-levels
#2
https://www.readbyqxmd.com/read/29850527/-drosophila-melanogaster-models-of-friedreich-s-ataxia
#3
REVIEW
P Calap-Quintana, J A Navarro, J González-Fernández, M J Martínez-Sebastián, M D Moltó, J V Llorens
Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29794127/adding-a-temporal-dimension-to-the-study-of-friedreich-s-ataxia-the-effect-of-frataxin-overexpression-in-a-human-cell-model
#4
Tommaso Vannocci, Roberto Notario Manzano, Ombretta Beccalli, Barbara Bettegazzi, Fabio Grohovaz, Gianfelice Cinque, Antonio de Riso, Luca Quaroni, Franca Codazzi, Annalisa Pastore
The neurodegenerative disease Friedreich's ataxia is caused by lower than normal levels of frataxin, an important protein involved in iron sulphur cluster biogenesis. An important step in designing strategies to treat this disease is to understand whether increasing the frataxin levels by gene therapy would be tout-court beneficial or detrimental since previous studies, mostly based on animal models, have reported conflicting results. Here, we have exploited an inducible model, which we developed using the CRISPR/Cas9 methodology, to study the effects of frataxin overexpression in human cells and follow how the system recovers after overexpression...
May 24, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29773647/altered-sterol-metabolism-in-budding-yeast-affects-mitochondrial-iron-sulfur-fe-s-cluster-synthesis
#5
Diane M Ward, Opal S Chen, Liangtao Li, Jerry Kaplan, Shah Alam Bhuiyan, Selvamuthu K Natarajan, Martin Bard, James E Cox
Ergosterol synthesis is essential for cellular growth and viability of the budding yeast Saccharomyces cerevisiae, and intracellular sterol distribution and homeostasis are therefore highly regulated in this species. Erg25 is an iron-containing C4-methyl sterol oxidase that contributes to the conversion of 4,4-dimethylzymosterol to zymosterol, a precursor of ergosterol. The ERG29 gene encodes an endoplasmic reticulum (ER)-associated protein, and here we identified a role for Erg29 in the methyl sterol oxidase step of ergosterol synthesis...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29773347/lipophilic-methylene-blue-analogues-enhance-mitochondrial-function-and-increase-frataxin-levels-in-a-cellular-model-of-friedreich-s-ataxia
#6
Omar M Khdour, Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P Visavadiya, Sidney M Hecht
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders...
May 4, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29666341/genetic-testing-for-clinically-suspected-spinocerebellar-ataxias-report-from-a-tertiary-referral-centre-in-india
#7
Sowmya Devatha Venkatesh, Mahesh Kandasamy, Nagaraj S Moily, Radhika Vaidyanathan, Lakshmi Narayanan Kota, Syama Adhikarla, Ravi Yadav, Pramod Kumar Pal, Sanjeev Jain, Meera Purushottam
Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative syndromes, characterized by a wide range of muscular weakness and motor deficits, caused due to cerebellar degeneration. The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA...
March 2018: Journal of Genetics
https://www.readbyqxmd.com/read/29625173/brain-mitochondrial-iron-accumulates-in-huntington-s-disease-mediates-mitochondrial-dysfunction-and-can-be-removed-pharmacologically
#8
Sonal Agrawal, Julia Fox, Baskaran Thyagarajan, Jonathan H Fox
Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin...
May 20, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29623423/clinical-and-genetic-aspects-of-defects-in-the-mitochondrial-iron-sulfur-cluster-synthesis-pathway
#9
REVIEW
A V Vanlander, R Van Coster
Iron-sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron-sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron-sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich's ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported...
April 5, 2018: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/29610276/the-transcriptional-regulator-ccctc-binding-factor-limits-oxidative-stress-in-endothelial-cells
#10
Anna R Roy, Abdalla Ahmed, Peter V DiStefano, Lijun Chi, Nadiya Khyzha, Niels Galjart, Michael D Wilson, Jason E Fish, Paul Delgado-Olguín
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 because of defective yolk sac and placental vascular development...
June 1, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29576242/interactions-of-iron-bound-frataxin-with-iscu-and-ferredoxin-on-the-cysteine-desulfurase-complex-leading-to-fe-s-cluster-assembly
#11
Kai Cai, Ronnie O Frederick, Marco Tonelli, John L Markley
Frataxin (FXN) is involved in mitochondrial iron‑sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry and multinuclear NMR spectroscopy to investigate interactions among the components of the biological machine that carries out the assembly of iron‑sulfur clusters in human mitochondria. Our results show that FXN tightly binds a single Fe2+ but not Fe3+ ...
June 2018: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29576218/mutations-in-pmpcb-encoding-the-catalytic-subunit-of-the-mitochondrial-presequence-protease-cause-neurodegeneration-in-early-childhood
#12
F-Nora Vögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W Friederich, Susan M White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A Jähn, Oliver Keminer, Katherine L Helbig, Carolyn F Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu, Deepali N Shinde, Ulrich Stephani, Johan L K Van Hove, Franz-Josef Müller, Ingo Helbig
Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins...
April 5, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29572489/iron-regulatory-protein-deficiency-compromises-mitochondrial-function-in-murine-embryonic-fibroblasts
#13
Huihui Li, Hongting Zhao, Shuangying Hao, Longcheng Shang, Jing Wu, Chuanhui Song, Esther G Meyron-Holtz, Tong Qiao, Kuanyu Li
Iron is essential for growth and proliferation of mammalian cells. The maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs) through binding to the cognate iron-responsive elements in target mRNAs and thereby regulating the expression of target genes. Irp1 or Irp2-null mutation is known to reduce the cellular iron level by decreasing transferrin receptor 1 and increasing ferritin. Here, we report that Irp1 or Irp2-null mutation also causes downregulation of frataxin and IscU, two of the core components in the iron-sulfur cluster biogenesis machinery...
March 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29568068/identification-of-p38-mapk-as-a-novel-therapeutic-target-for-friedreich-s-ataxia
#14
M Grazia Cotticelli, Shujuan Xia, Avinash Kaur, Daniel Lin, Yongping Wang, Eric Ruff, John W Tobias, Robert B Wilson
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence...
March 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29563863/mitofusin-dependent-er-stress-triggers-glial-dysfunction-and-nervous-system-degeneration-in-a-drosophila-model-of-friedreich-s-ataxia
#15
Oliver Edenharter, Stephan Schneuwly, Juan A Navarro
Friedreich's ataxia (FRDA) is the most important recessive ataxia in the Caucasian population. It is caused by a deficit of the mitochondrial protein frataxin. Despite its pivotal effect on biosynthesis of iron-sulfur clusters and mitochondrial energy production, little is known about the influence of frataxin depletion on homeostasis of the cellular mitochondrial network. We have carried out a forward genetic screen to analyze genetic interactions between genes controlling mitochondrial homeostasis and Drosophila frataxin...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29555919/frataxin-overexpression-in-m%C3%A3-ller-cells-protects-retinal-ganglion-cells-in-a-mouse-model-of-ischemia-reperfusion-injury-in-vivo
#16
Rowena Schultz, Melanie Krug, Michel Precht, Stefanie G Wohl, Otto W Witte, Christian Schmeer
Müller cells are critical for retinal function and neuronal survival but can become detrimental in response to retinal ischemia and increased oxidative stress. Elevated oxidative stress increases expression of the mitochondrial enzyme frataxin in the retina, and its overexpression is neuroprotective after ischemia. Whether frataxin expression in Müller cells might improve their function and protect neurons after ischemia is unknown. The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo...
March 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29534309/bone-marrow-transplantation-stimulates-neural-repair-in-friedreich-s-ataxia-mice
#17
Kevin C Kemp, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark A Pook, Claire M Rice, Neil J Scolding, Alastair Wilkins
OBJECTIVE: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here, we report the neuroreparative effects of myeloablative allogeneic bone marrow transplantation in a humanized murine model of the disease. METHODS: Mice received a transplant of fluorescently tagged sex-mismatched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioral motor performance tests...
April 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29511616/biophysical-characterisation-of-the-recombinant-human-frataxin-precursor
#18
Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini, Javier Santos
Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81-210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1-210). We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29499876/progress-in-the-treatment-of-friedreich-ataxia
#19
REVIEW
Geneieve Tai, Louise A Corben, Eppie M Yiu, Sarah C Milne, Martin B Delatycki
Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways...
March 2018: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/29491838/iron-sulfur-and-molybdenum-cofactor-enzymes-regulate-the-drosophila-life-cycle-by-controlling-cell-metabolism
#20
Zvonimir Marelja, Silke Leimkühler, Fanis Missirlis
Iron sulfur (Fe-S) clusters and the molybdenum cofactor (Moco) are present at enzyme sites, where the active metal facilitates electron transfer. Such enzyme systems are soluble in the mitochondrial matrix, cytosol and nucleus, or embedded in the inner mitochondrial membrane, but virtually absent from the cell secretory pathway. They are of ancient evolutionary origin supporting respiration, DNA replication, transcription, translation, the biosynthesis of steroids, heme, catabolism of purines, hydroxylation of xenobiotics, and cellular sulfur metabolism...
2018: Frontiers in Physiology
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