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Frataxin

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https://www.readbyqxmd.com/read/29223733/mitochondrial-pore-opening-and-loss-of-ca2-exchanger-nclx-levels-occur-after-frataxin-depletion
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/29053830/friedreich-s-ataxia-clinical-features-pathogenesis-and-management
#12
A Cook, P Giunti
Introduction: Friedreich's ataxia is the most common inherited ataxia. Sources of data: Literature search using PubMed with keywords Friedreich's ataxia together with published papers known to the authors. Areas of agreement: The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets...
October 19, 2017: British Medical Bulletin
https://www.readbyqxmd.com/read/29046887/erratum-selected-missense-mutations-impair-frataxin-processing-in-friedreich-ataxia
#13
(no author information available yet)
[This corrects the article DOI: 10.1002/acn3.433.].
October 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29044877/sustained-fxn-expression-in-dorsal-root-ganglia-from-a-nonreplicative-genomic-hsv-1-vector
#14
Maria Ventosa, Zetang Wu, Filip Lim
BACKGROUND: Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently there is no effective cure. METHODS: With the aim of developing a gene therapy for FA neuropathology, here we describe the construction and preliminary characterization of a high capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B-FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1...
October 17, 2017: Journal of Gene Medicine
https://www.readbyqxmd.com/read/29044418/friedreich-ataxia-developmental-failure-of-the-dorsal-root-entry-zone
#15
Arnulf H Koeppen, Alyssa B Becker, Jiang Qian, Benjamin B Gelman, Joseph E Mazurkiewicz
Dorsal root ganglia, dorsal roots (DR), and dorsal root entry zones (DREZ) are vulnerable to frataxin deficiency in Friedreich ataxia (FA). A previously unrecognized abnormality is the intrusion of astroglial tissue into DR. Segments of formalin-fixed upper lumbar spinal cord of 13 homozygous and 2 compound heterozygous FA patients were sectioned longitudinally to represent DREZ and stained for glial fibrillary acidic protein (GFAP), S100, vimentin, the central nervous system (CNS)-specific myelin protein proteolipid protein, the peripheral nervous system (PNS) myelin proteins PMP-22 and P0, and the Schwann cell proteins laminin, alpha-dystroglycan, and periaxin...
November 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28980774/frataxin-deficient-neurons-and-mice-models-of-friedreich-ataxia-are-improved-by-tat-mtscs-fxn-treatment
#16
Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros
Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans-activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT-MTScs-FXN fusion protein to decrease neurodegeneration markers on frataxin-depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues...
October 5, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28935570/molecular-alterations-in-a-mouse-cardiac-model-of-friedreich-ataxia-an-impaired-nuclear-factor-erythroid-2-related-factor-2-response-mediated-via-upregulation-of-kelch-like-ech-associated-protein-1-and-activation-of-the-glycogen%C3%A2-synthase-kinase-3%C3%AE-axis
#17
Amy Anzovino, Shannon Chiang, Bronwyn E Brown, Clare L Hawkins, Des R Richardson, Michael L-H Huang
Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, whereas skeletal muscle was asymptomatic...
September 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28931050/saxs-and-stability-studies-of-iron-induced-oligomers-of-bacterial-frataxin-cyay
#18
Mostafa Fekry, Wessen Alshokry, Przemysław Grela, Marek Tchórzewski, Eva-Christina Ahlgren, Christopher A Söderberg, Oleksandr Gakh, Grazia Isaya, Salam Al-Karadaghi
Frataxin is a highly conserved protein found in both prokaryotes and eukaryotes. It is involved in several central functions in cells, which include iron delivery to biochemical processes, such as heme synthesis, assembly of iron-sulfur clusters (ISC), storage of surplus iron in conditions of iron overload, and repair of ISC in aconitase. Frataxin from different organisms has been shown to undergo iron-dependent oligomerization. At least two different classes of oligomers, with different modes of oligomer packing and stabilization, have been identified...
2017: PloS One
https://www.readbyqxmd.com/read/28918000/nitric-oxide-prevents-aft1-activation-and-metabolic-remodeling-in-frataxin-deficient-yeast
#19
David Alsina, Joaquim Ros, Jordi Tamarit
Yeast frataxin homolog (Yfh1) is the orthologue of human frataxin, a mitochondrial protein whose deficiency causes Friedreich Ataxia. Yfh1 deficiency activates Aft1, a transcription factor governing iron homeostasis in yeast cells. Although the mechanisms causing this activation are not completely understood, it is assumed that it may be caused by iron-sulfur deficiency. However, several evidences indicate that activation of Aft1 occurs in the absence of iron-sulfur deficiency. Besides, Yfh1 deficiency also leads to metabolic remodeling (mainly consisting in a shift from respiratory to fermentative metabolism) and to induction of Yhb1, a nitric oxide (NO) detoxifying enzyme...
September 6, 2017: Redox Biology
https://www.readbyqxmd.com/read/28912677/reversible-axonal-dystrophy-by-calcium-modulation-in-frataxin-deficient-sensory-neurons-of-yg8r-mice
#20
Belén Mollá, Diana C Muñoz-Lasso, Fátima Riveiro, Arantxa Bolinches-Amorós, Federico V Pallardó, Angel Fernandez-Vilata, María de la Iglesia-Vaya, Francesc Palau, Pilar Gonzalez-Cabo
Friedreich's ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux...
2017: Frontiers in Molecular Neuroscience
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