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Frataxin

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https://www.readbyqxmd.com/read/28412459/no-changes-in-heme-synthesis-in-human-friedreich%C3%A2-s-ataxia-erythroid-progenitor-cells
#1
Hannes Steinkellner, Himanshu Narayan Singh, Martina U Muckenthaler, Hans Goldenberg, Rajeswari R Moganty, Barbara Scheiber-Mojdehkar, Brigitte Sturm
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the protein frataxin. Frataxin is thought to play a role in iron-sulfur cluster biogenesis and heme synthesis. In this study, we used erythroid progenitor stem cells obtained from FRDA patients and healthy donors to investigate the putative role, if any, of frataxin deficiency in heme synthesis. We used electrochemiluminescence and qRT-PCR for frataxin protein and mRNA quantification. We used atomic absorption spectrophotometry for iron levels and a photometric assay for hemoglobin levels...
April 12, 2017: Gene
https://www.readbyqxmd.com/read/28405347/friedreich-ataxia-current-status-and-future-prospects
#2
REVIEW
Katrin Bürk
Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies...
2017: Cerebellum & Ataxias
https://www.readbyqxmd.com/read/28286293/a-role-for-astrocytes-in-cerebellar-deficits-in-frataxin-deficiency-protection-by-insulin-like-growth-factor-i
#3
C Franco, L Genis, J A Navarro, P Perez-Domper, A M Fernandez, S Schneuwly, I Torres Alemán
Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions...
March 7, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28282710/early-onset-friedreich-s-ataxia-with-oculomotor-apraxia
#4
Amene Saghazadeh, Sina Hafizi, Firouzeh Hosseini, Mahmoud Reza Ashrafi, Nima Rezaei
Friedreich's ataxia (FRDA) is a rare autosomal recessive spinocerebellar ataxia which in the majority of cases is associated with a GAA-trinucleotide repeat expansion in the first intron of Frataxin gene located on chromosome 9. The clinical features include progressive gait and limb ataxia, cerebellar dysarthria, neuropathy, optic atrophy, and loss of vibration and proprioception. Ataxia with ocular motor apraxia type 1 (AOA1) is another autosomal recessive cerebellar ataxia which is associated with oculomotor apraxia, hypoalbuminaemia, and hypercholesterolemia...
February 2017: Acta Medica Iranica
https://www.readbyqxmd.com/read/28271877/the-n-terminus-of-iron-sulfur-cluster-assembly-factor-isd11-is-crucial-for-subcellular-targeting-and-interaction-with-l-cysteine-desulfurase-nfs1
#5
Martin Friemel, Zvonimir Marelja, Kuanyu Li, Silke Leimkühler
Assembly of iron-sulfur (FeS) clusters is an important process in living cells. The initial sulfur mobilization step for FeS cluster biosynthesis is catalyzed by l-cysteine desulfurase NFS1, a reaction that is localized in mitochondria in humans. In humans, the function of NFS1 depends on the ISD11 protein, which is required to stabilize its structure. The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for FeS cluster formation...
March 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/28228265/e3-ligase-rnf126-directly-ubiquitinates-frataxin-promoting-its-degradation-identification-of-a-potential-therapeutic-target-for-friedreich-ataxia
#6
Monica Benini, Silvia Fortuni, Ivano Condò, Giulia Alfedi, Florence Malisan, Nicola Toschi, Dario Serio, Damiano Sergio Massaro, Gaetano Arcuri, Roberto Testi, Alessandra Rufini
Friedreich ataxia (FRDA) is a severe genetic neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. To date, there is no therapy to treat this condition. The amount of residual frataxin critically affects the severity of the disease; thus, attempts to restore physiological frataxin levels are considered therapeutically relevant. Frataxin levels are controlled by the ubiquitin-proteasome system; therefore, inhibition of the frataxin E3 ligase may represent a strategy to achieve an increase in frataxin levels...
February 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28024081/deletion-of-the-gaa-repeats-from-the-human-frataxin-gene-using-the-crispr-cas9-system-in-yg8r-derived-cells-and-mouse-models-of-friedreich-ataxia
#7
D L Ouellet, K Cherif, J Rousseau, J P Tremblay
The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo...
January 19, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28009062/cytokine-therapy-mediated-neuroprotection-in-a-friedreich-s-ataxia-mouse-model
#8
Kevin C Kemp, Nadia Cerminara, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark Pook, Richard Apps, Neil J Scolding, Alastair Wilkins
OBJECTIVES: Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. METHODS: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests...
February 2017: Annals of Neurology
https://www.readbyqxmd.com/read/27941692/liver-growth-factor-lgf-upregulates-frataxin-protein-expression-and-reduces-oxidative-stress-in-friedreich-s-ataxia-transgenic-mice
#9
Lucía Calatrava-Ferreras, Rafael Gonzalo-Gobernado, Diana Reimers, Antonio S Herranz, María J Casarejos, Adriano Jiménez-Escrig, Javier Regadera, Juan Velasco-Martín, Manuela Vallejo-Muñoz, Juan José Díaz-Gil, Eulalia Bazán
Friedreich's ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA...
December 9, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27901468/loss-of-frataxin-activates-the-iron-sphingolipid-pdk1-mef2-pathway-in-mammals
#10
Kuchuan Chen, Tammy Szu-Yu Ho, Guang Lin, Kai Li Tan, Matthew N Rasband, Hugo J Bellen
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations in Frataxin (FXN). Loss of FXN causes impaired mitochondrial function and iron homeostasis. An elevated production of reactive oxygen species (ROS) was previously proposed to contribute to the pathogenesis of FRDA. We recently showed that loss of frataxin homolog (fh), a Drosophila homolog of FXN, causes a ROS independent neurodegeneration in flies (Chen et al., 2016). In fh mutants, iron accumulation in the nervous system enhances the synthesis of sphingolipids, which in turn activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2) to trigger neurodegeneration of adult photoreceptors...
November 30, 2016: ELife
https://www.readbyqxmd.com/read/27846236/disruption-of-higher-order-dna-structures-in-friedreich-s-ataxia-gaa-n-repeats-by-pna-or-lna-targeting
#11
Helen Bergquist, Cristina S J Rocha, Rubén Álvarez-Asencio, Chi-Hung Nguyen, Mark W Rutland, C I Edvard Smith, Liam Good, Peter E Nielsen, Rula Zain
Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions...
2016: PloS One
https://www.readbyqxmd.com/read/27802581/essential-dynamics-of-the-cold-denaturation-pressure-and-temperature-effects-in-yeast-frataxin
#12
Yanis R Espinosa, J Raúl Grigera, Ernesto R Caffarena
The cold denaturation of globular proteins is a process that can be caused by increasing pressure or decreasing the temperature. Currently, the action mechanism of this process has not been clearly understood, raising an interesting debate on the matter. We have studied the process of cold denaturation using molecular dynamics simulations of the frataxin system Yfh1, which has a dynamic experimental characterization of unfolding at low and high temperatures. The frataxin model here studied allows a comparative analysis using experimental data...
January 2017: Proteins
https://www.readbyqxmd.com/read/27771440/heterologous-mitochondrial-targeting-sequences-can-deliver-functional-proteins-into-mitochondria
#13
Dana Marcus, Michal Lichtenstein, Natali Cohen, Rita Hadad, Tal Erlich-Hadad, Hagar Greif, Haya Lorberboum-Galski
Mitochondrial Targeting Sequences (MTSs) are responsible for trafficking nuclear-encoded proteins into mitochondria. Once entering the mitochondria, the MTS is recognized and cleaved off. Some MTSs are long and undergo two-step processing, as in the case of the human frataxin (FXN) protein (80aa), implicated in Friedreich's ataxia (FA). Therefore, we chose the FXN protein to examine whether nuclear-encoded mitochondrial proteins can efficiently be targeted via a heterologous MTS (hMTS) and deliver a functional protein into mitochondria...
December 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27738674/in-vitro-characterization-of-a-novel-isu-homologue-from-drosophila-melanogaster-for-de-novo-fes-cluster-formation
#14
Stephen P Dzul, Agostinho G Rocha, Swati Rawat, Ashoka Kandegedara, April Kusowski, Jayashree Pain, Anjaneyulu Murari, Debkumar Pain, Andrew Dancis, Timothy L Stemmler
FeS-clusters are utilized by numerous proteins within several biological pathways that are essential for life. In eukaryotes, the primary FeS-cluster production pathway is the mitochondrial iron-sulfur cluster (ISC) pathway. In Saccharomyces cerevisiae, de novo FeS-cluster formation is accomplished through coordinated assembly with the substrates iron and sulfur by the scaffold assembly protein "Isu1". Sulfur for cluster assembly is provided by cysteine desulfurase "Nfs1", a protein that works in union with its accessory protein "Isd11"...
January 25, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/27730125/a-new-tessera-into-the-interactome-of-the-isc-operon-a-novel-interaction-between-hscb-and-iscs
#15
Rita Puglisi, Robert Yan, Salvatore Adinolfi, Annalisa Pastore
Iron sulfur clusters are essential universal prosthetic groups which can be formed inorganically but, in biology, are bound to proteins and produced enzymatically. Most of the components of the machine that produces the clusters are conserved throughout evolution. In bacteria, they are encoded in the isc operon. Previous reports provide information on the role of specific components but a clear picture of how the whole machine works is still missing. We have carried out a study of the effects of the co-chaperone HscB from the model system E...
2016: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/27668106/atypical-features-in-a-large-turkish-family-affected-with-friedreich-ataxia
#16
Semiha Kurt, Betul Cevik, Durdane Aksoy, E Irmak Sahbaz, Aslı Gundogdu Eken, A Nazli Basak
Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient...
2016: Case Reports in Neurological Medicine
https://www.readbyqxmd.com/read/27615158/alleviating-gaa-repeat-induced-transcriptional-silencing-of-the-friedreich-s-ataxia-gene-during-somatic-cell-reprogramming
#17
Urszula Polak, Yanjie Li, Jill Sergesketter Butler, Marek Napierala
Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. This severe neurodegenerative disease is caused by an expansion of guanine-adenine-adenine (GAA) repeats located in the first intron of the frataxin (FXN) gene, which represses its transcription. Although transcriptional silencing is associated with heterochromatin-like changes in the vicinity of the expanded GAAs, the exact mechanism and pathways involved in transcriptional inhibition are largely unknown. As major remodeling of the epigenome is associated with somatic cell reprogramming, modulating chromatin modification pathways during the cellular transition from a somatic to a pluripotent state is likely to generate permanent changes to the epigenetic landscape...
December 1, 2016: Stem Cells and Development
https://www.readbyqxmd.com/read/27594434/friedreich-ataxia-induced-pluripotent-stem-cell-derived-neurons-show-a-cellular-phenotype-that-is-corrected-by-a-benzamide-hdac-inhibitor
#18
Franca Codazzi, Amelié Hu, Myriam Rai, Floramarida Salerno Scarzella, Elisabeth Mangiameli, Ilaria Pelizzoni, Fabio Grohovaz, Massimo Pandolfo
We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron-sulfur and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared to CT neurons, indicating deficient iron-sulfur cluster biogenesis, altered iron metabolism, and oxidative stress...
September 4, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27575947/neurobehavioral-deficits-in-the-kiko-mouse-model-of-friedreich-s-ataxia
#19
Marissa Z McMackin, Chelsea K Henderson, Gino A Cortopassi
Friedreich's Ataxia (FA) is a pediatric neurodegenerative disease whose clinical presentation includes ataxia, muscle weakness, and peripheral sensory neuropathy. The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA, which currently has no approved therapy. We tested 13 neurobehavioral tasks to identify a robust KIKO phenotype: Open Field, Grip Strength Test(s), Cylinder, Skilled Forelimb Grasp Task(s), Treadmill Endurance, Locotronic Motor Coordination, Inverted Screen, Treadscan, and Von Frey...
January 1, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/27537261/increased-frataxin-levels-protect-retinal-ganglion-cells-after-acute-ischemia-reperfusion-in-the-mouse-retina-in-vivo
#20
Rowena Schultz, Otto W Witte, Christian Schmeer
PURPOSE: The mitochondrial protein frataxin (FXN) is highly expressed in metabolically active tissues and has been shown to improve cell survival in response to oxidative stress after ischemia. Retinal ischemia/hypoxia is a complication of ocular diseases such as diabetic retinopathy and glaucoma. There are no effective therapeutic approaches currently available. This study was performed to evaluate the neuroprotective effects of FXN after acute retinal ischemia/reperfusion in vivo. METHODS: Retinal ischemia/reperfusion was induced in adult wild-type and FXN-overexpressing mice by transient elevation of intraocular pressure (IOP) for 45 minutes...
August 1, 2016: Investigative Ophthalmology & Visual Science
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