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Frataxin

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https://www.readbyqxmd.com/read/29447225/low-apolipoprotein-a-i-levels-in-friedreich-s-ataxia-and-in-frataxin-deficient-cells-implications-for-therapy
#1
QingQing Wang, Lili Guo, Cassandra J Strawser, Lauren A Hauser, Wei-Ting Hwang, Nathaniel W Snyder, David R Lynch, Clementina Mesaros, Ian A Blair
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure...
2018: PloS One
https://www.readbyqxmd.com/read/29406711/iscu-m108i-and-iscu-d39v-differ-from-wild-type-iscu-in-their-failure-to-form-cysteine-desulfurase-complexes-containing-both-frataxin-and-ferredoxin
#2
Kai Cai, Ronnie O Frederick, Marco Tonelli, John L Markley
Whereas iron-sulfur (Fe-S) cluster assembly on the wild-type scaffold protein ISCU, as catalyzed by the human cysteine desulfurase complex (SDA), exhibits a requirement for frataxin (FXN), assembly on variant ISCU(M108I) has been shown to bypass the FXN requirement. Wild-type ISCU populates two interconverting conformational states: one structured and one dynamically disordered. We show here that ISCU(M108I) populates only the structured state as does another variant ISCU(D39V). We have compared the properties ISCU, ISCU(M108I), and ISCU(D39V), with and without FXN, in both the cysteine desulfurase step of Fe-S cluster assembly and in the overall Fe-S cluster assembly reaction...
February 6, 2018: Biochemistry
https://www.readbyqxmd.com/read/29341839/activation-of-frataxin-protein-expression-by-antisense-oligonucleotides-targeting-the-mutant-expanded-repeat
#3
Liande Li, Xiulong Shen, Zhongtian Liu, Michaela Norrbom, Thazha P Prakash, Daniel O'Reilly, Vivek K Sharma, Masad J Damha, Jonathan K Watts, Frank Rigo, David R Corey
Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA...
January 17, 2018: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/29329987/quantitative-proteomics-in-friedreich-s-ataxia-b-lymphocytes-a-valuable-approach-to-decipher-the-biochemical-events-responsible-for-pathogenesis
#4
Lorène Télot, Elodie Rousseau, Emmanuel Lesuisse, Camille Garcia, Bastien Morlet, Thibaut Léger, Jean-Michel Camadro, Valérie Serre
Friedreich's ataxia (FRDA) represents the most frequent type of autosomal-recessively inherited ataxia and is caused by the deficiency of frataxin, a mitochondrial protein. It is known that frataxin-deficiency leads to alterations in cellular and mitochondrial iron metabolism and impacts in the cell physiology at several levels. Frataxin is thought to play a role in iron-sulfur cluster biogenesis and heme synthesis. Currently, cellular antioxidant defense is dysregulated when frataxin is deficient, which exacerbates oxidative damage in FRDA...
January 9, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29325611/autosomal-recessive-cerebellar-ataxias
#5
Brent L Fogel
The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29325032/effect-of-diazoxide-on-friedreich-ataxia-models
#6
Antonella Santoro, Sara Anjomani Virmouni, Eleonora Paradies, Valentina L Villalobos Coa, Sahar Al-Mahdawi, Mee Khoo, Vito Porcelli, Angelo Vozza, Mara Perrone, Nunzio Denora, Franco Taroni, Giuseppe Merla, Luigi Palmieri, Mark A Pook, Carlo M T Marobbio
Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for FRDA available, especially for neurological deficits. In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mTOR pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy...
January 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29277024/copper-redox-chemistry-of-plant-frataxins
#7
Manu Sánchez, Òscar Palacios, Celeste Buchensky, Laura Sabio, Diego Fabian Gomez-Casati, Maria Ayelen Pagani, Mercè Capdevila, Silvia Atrian, Jose M Dominguez-Vera
The presence of a conserved cysteine residue in the C-terminal amino acid sequences of plant frataxins differentiates these frataxins from those of other kingdoms and may be key in frataxin assembly and function. We report a full study on the ability of Arabidopsis (AtFH) and Zea mays (ZmFH-1 and ZmFH-2) frataxins to assemble into disulfide-bridged dimers by copper-driven oxidation and to revert to monomers by chemical reduction. We monitored the redox assembly-disassembly process by electrospray ionization mass spectrometry, electrophoresis, UV-Vis spectroscopy, and fluorescence measurements...
November 27, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29261783/somatic-instability-of-the-expanded-gaa-repeats-in-friedreich-s-ataxia
#8
Ashlee Long, Jill S Napierala, Urszula Polak, Lauren Hauser, Arnulf H Koeppen, David R Lynch, Marek Napierala
Friedreich's ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA repeats in intron 1. FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression...
2017: PloS One
https://www.readbyqxmd.com/read/29259026/early-vglut1-specific-parallel-fiber-synaptic-deficits-and-dysregulated-cerebellar-circuit-in-the-kiko-mouse-model-of-friedreich-ataxia
#9
Hong Lin, Jordi Magrane, Elisia M Clark, Sarah M Halawani, Nathan Warren, Amy Rattelle, David R Lynch
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model...
December 19, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29223733/mitochondrial-pore-opening-and-loss-of-ca2-exchanger-nclx-levels-occur-after-frataxin-depletion
#10
R Purroy, E Britti, F Delaspre, J Tamarit, J Ros
Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons...
December 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29200434/iron-induced-oligomerization-of-human-fxn81-210-and-bacterial-cyay-frataxin-and-the-effect-of-iron-chelators
#11
Eva-Christina Ahlgren, Mostafa Fekry, Mathias Wiemann, Christopher A Söderberg, Katja Bernfur, Olex Gakh, Morten Rasmussen, Peter Højrup, Cecilia Emanuelsson, Grazia Isaya, Salam Al-Karadaghi
Patients suffering from the progressive neurodegenerative disease Friedreich's ataxia have reduced expression levels of the protein frataxin. Three major isoforms of human frataxin have been identified, FXN42-210, FXN56-210 and FXN81-210, of which FXN81-210 is considered to be the mature form. Both long forms, FXN42-210 and FXN56-210, have been shown to spontaneously form oligomeric particles stabilized by the extended N-terminal sequence. The short variant FXN81-210, on other hand, has only been observed in the monomeric state...
2017: PloS One
https://www.readbyqxmd.com/read/29197070/the-role-of-oxidative-stress-in-friedreich-s-ataxia
#12
REVIEW
Federica Lupoli, Tommaso Vannocci, Giovanni Longo, Neri Niccolai, Annalisa Pastore
Oxidative stress and increase in the levels of free radicals are important markers associated with several pathologies, including Alzheimer's disease, cancer and diabetes. Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role. Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia...
December 2, 2017: FEBS Letters
https://www.readbyqxmd.com/read/29192133/synthetic-transcription-elongation-factors-license-transcription-across-repressive-chromatin
#13
Graham S Erwin, Matthew P Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, Katie Worringer, Rajeev Sivasankaran, Deeba N Syed, Asuka Eguchi, Md Ashraf, Justin Jeffery, Mousheng Xu, Paul M C Park, Hasan Mukhtar, Achal K Srivastava, Mohammed Faruq, James E Bradner, Aseem Z Ansari
Releasing a paused RNA polymerase II into productive elongation is tightly-regulated, especially at genes that impact human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators...
November 30, 2017: Science
https://www.readbyqxmd.com/read/29125828/comprehensive-analysis-of-gene-expression-patterns-in-friedreich-s-ataxia-fibroblasts-by-rna-sequencing-reveals-altered-levels-of-protein-synthesis-factors-and-solute-carriers
#14
Jill Sergesketter Napierala, Yanjie Li, Yue Lu, Kevin Lin, Lauren A Hauser, David R Lynch, Marek Napierala
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron-sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29125827/early-cerebellar-deficits-in-mitochondrial-biogenesis-and-respiratory-chain-complexes-in-the-kiko-mouse-model-of-friedreich-ataxia
#15
Hong Lin, Jordi Magrane, Amy Rattelle, Anna Stepanova, Alexander Galkin, Elisia M Clark, Yi Na Dong, Sarah M Halawani, David R Lynch
Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29097656/structure-and-functional-dynamics-of-the-mitochondrial-fe-s-cluster-synthesis-complex
#16
Michal T Boniecki, Sven A Freibert, Ulrich Mühlenhoff, Roland Lill, Miroslaw Cygler
Iron-sulfur (Fe/S) clusters are essential protein cofactors crucial for many cellular functions including DNA maintenance, protein translation, and energy conversion. De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1, ferredoxin, frataxin, and the small factors ISD11 and ACP (acyl carrier protein). Both the mechanism of Fe/S cluster synthesis and function of ISD11-ACP are poorly understood. Here, we present crystal structures of three different NFS1-ISD11-ACP complexes with and without ISCU, and we use SAXS analyses to define the 3D architecture of the complete mitochondrial Fe/S cluster biosynthetic complex...
November 3, 2017: Nature Communications
https://www.readbyqxmd.com/read/29097312/insights-on-the-conformational-dynamics-of-human-frataxin-through-modifications-of-loop-1
#17
Martín E Noguera, Martín Aran, Clara Smal, Diego S Vazquez, María Georgina Herrera, Ernesto A Roman, Nadine Alaimo, Mariana Gallo, Javier Santos
Human frataxin (FXN) is a highly conserved mitochondrial protein involved in iron homeostasis and activation of the iron-sulfur cluster assembly. FXN deficiency causes the neurodegenerative disease Friedreich's Ataxia. Here, we investigated the effect of alterations in loop-1, a stretch presumably essential for FXN function, on the conformational stability and dynamics of the native state. We generated four loop-1 variants, carrying substitutions, insertions and deletions. All of them were stable and well-folded proteins...
October 30, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29090418/chemical-shift-assignment-of-a-thermophile-frataxin
#18
Masooma Rasheed, Robert Yan, Geoff Kelly, Annalisa Pastore
Frataxin is the protein responsible for the genetically-inherited neurodegenerative disease Friedreich's ataxia caused by partial silencing of the protein and loss of function. Although the frataxin function is not yet entirely clear, it has been associated to the machine that builds iron-sulfur clusters, essential prosthetic groups involved in several processes and is strongly conserved in organisms from bacteria to humans. Two of its important molecular partners are the protein NFS1 (or IscS in bacteria), that is the desulfurase which converts cysteine to alanine and produces sulfur, and ISU (or IscU), the scaffold protein which transiently accepts the cluster...
October 31, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29070698/transplantation-of-wild-type-mouse-hematopoietic-stem-and-progenitor-cells-ameliorates-deficits-in-a-mouse-model-of-friedreich-s-ataxia
#19
Celine J Rocca, Spencer M Goodman, Jennifer N Dulin, Joseph H Haquang, Ilya Gertsman, Jordan Blondelle, Janell L M Smith, Charles J Heyser, Stephanie Cherqui
Friedreich's ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29057804/nrf2-inducers-counteract-neurodegeneration-in-frataxin-silenced-motor-neurons-disclosing-new-therapeutic-targets-for-friedreich-s-ataxia
#20
Sara Petrillo, Emanuela Piermarini, Anna Pastore, Gessica Vasco, Tommaso Schirinzi, Rosalba Carrozzo, Enrico Bertini, Fiorella Piemonte
Oxidative stress is actively involved in Friedreich's Ataxia (FA), thus pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor Nrf2 on frataxin-deficient cultured motor neurons and on fibroblasts of patients. The in vitro treatment of the potent Nrf2 activator sulforaphane increased Nrf2 protein levels and led to the upregulation of phase II antioxidant enzymes. The neuroprotective effects were accompanied by an increase in neurites' number and extension...
October 18, 2017: International Journal of Molecular Sciences
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