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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"...
October 14, 2016: Metallomics: Integrated Biometal Science
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
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
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...
October 17, 2016: Stem Cells and Development
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
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
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
H Khonsari, M Schneider, S Al-Mahdawi, Y G Chianea, M Themis, C Parris, M A Pook, M Themis
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia (DRG) and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron-sulphur cluster (ISC) biogenesis and low frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species (ROS) and sensitivity to oxidative stress...
August 12, 2016: Gene Therapy
Emanuela Piermarini, Daniele Cartelli, Anna Pastore, Giulia Tozzi, Claudia Compagnucci, Ezio Giorda, Jessica D'Amico, Stefania Petrini, Enrico Bertini E, Graziella Cappelletti, Fiorella Piemonte
To elucidate the pathogenesis of axonopathy in Friedreich's Ataxia (FRDA), a neurodegenerative disease characterized by axonal retraction, we analyzed the microtubule (MT) dynamics in an in vitro frataxin-silenced neuronal model (shFxn). A typical feature of MTs is their "dynamic instability", in which they undergo phases of growth (polymerization) and shrinkage (depolymerization). MTs play a fundamental role in the physiology of neurons and every perturbation of their dynamicity is highly detrimental for neuronal functions...
August 11, 2016: Human Molecular Genetics
Shaista Parveen, Deepti Bhushan Gupta, Suchismita Dass, Amit Kumar, Aarti Pandey, Subhra Chakraborty, Niranjan Chakraborty
Ferritins store and sequester iron, and regulate iron homeostasis. The cDNA for a stress-responsive phytoferritin, previously identified in the extracellular matrix (ECM) of chickpea (Cicer arietinum), was cloned and designated CaFer1. The CaFer1 transcript was strongly induced in chickpea exposed to dehydration, hypersalinity and ABA treatment. Additionally, it has role in the defense against Fusarium oxysporum infection. Functional complementation of the yeast frataxin-deficient mutant, Δyfh1, indicates that CaFer1 functions in oxidative stress...
2016: Scientific Reports
Antonio Costantini, Tiziana Laureti, Maria Immacolata Pala, Marco Colangeli, Simona Cavalieri, Elisa Pozzi, Alfredo Brusco, Sandro Salvarani, Carlo Serrati, Roberto Fancellu
Thiamine (vitamin B1) is a cofactor of fundamental enzymes of cell energetic metabolism; its deficiency causes disorders affecting both the peripheral and central nervous system. Previous studies reported low thiamine levels in cerebrospinal fluid and pyruvate dehydrogenase dysfunction in Friedreich ataxia (FRDA). We investigated the effect of long-term treatment with thiamine in FRDA, evaluating changes in neurological symptoms, echocardiographic parameters, and plasma FXN mRNA levels. Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment...
November 2016: Journal of Neurology
David R Corey
Importance: The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease. Objective: To review the use of ASOs for the treatment of neurological disorders. Evidence Review: Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich's ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy)...
October 1, 2016: JAMA Neurology
Martina Stevanoni, Elisa Palumbo, Antonella Russo
It is well known that DNA replication affects the stability of several trinucleotide repeats, but whether replication profiles of human loci carrying an expanded repeat differ from those of normal alleles is poorly understood in the endogenous context. We investigated this issue using cell lines from Friedreich's ataxia patients, homozygous for a GAA-repeat expansion in intron 1 of the Frataxin gene. By interphase, FISH we found that in comparison to the normal Frataxin sequence the replication of expanded alleles is slowed or delayed...
July 2016: PLoS Genetics
Sirena Soriano, Pablo Calap-Quintana, José Vicente Llorens, Ismael Al-Ramahi, Lucía Gutiérrez, María José Martínez-Sebastián, Juan Botas, María Dolores Moltó
Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance...
2016: PloS One
Jeannine Gerhardt, Angela D Bhalla, Jill Sergesketter Butler, James W Puckett, Peter B Dervan, Zev Rosenwaks, Marek Napierala
Friedreich's ataxia (FRDA) is caused by the expansion of GAA repeats located in the Frataxin (FXN) gene. The GAA repeats continue to expand in FRDA patients, aggravating symptoms and contributing to disease progression. The mechanism leading to repeat expansion and decreased FXN transcription remains unclear. Using single-molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells cause an increase in 3'-5' progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases...
August 2, 2016: Cell Reports
Arnulf H Koeppen, Alyssa B Becker, Paul J Feustel, Benjamin B Gelman, Joseph E Mazurkiewicz
Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling...
August 15, 2016: Journal of the Neurological Sciences
Angela D Bhalla, Alireza Khodadadi-Jamayran, Yanjie Li, David R Lynch, Marek Napierala
OBJECTIVE: Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat expansion disorder caused by epigenetic silencing of the frataxin gene (FXN). Current research suggests that damage and variation of mitochondrial DNA (mtDNA) contribute to the molecular pathogenesis of FRDA. We sought to establish the extent of the mutation burden across the mitochondrial genome in FRDA cells and investigate the molecular mechanisms connecting FXN downregulation and the acquisition of mtDNA damage...
July 2016: Annals of Clinical and Translational Neurology
Hideki Kawai, Shin-Ichiro Morimoto, Yoko Takakuwa, Akihiro Ueda, Ken-Ichi Inada, Masayoshi Sarai, Takuro Arimura, Tatsuro Mutoh, Akinori Kimura, Yukio Ozaki
We report the case of a 66 year-old woman with chronic atrial fibrillation, hypertrophic cardiomyopathy (HCM), and spinocerebellar atrophy (SCA). Her mother and first-born son had died of heart disease at the ages of 65 and 16 years, respectively. Four of her 8 siblings had died suddenly of unknown cause or of heart disease, and 2 others of cerebral infarction by the 7th decade. Genetic testing revealed that she had a novel mutation (c. 482C > A, p. Ala161Asp) in the troponin I gene (TNNI3), and no abnormality of the GAA repeat in the frataxin gene...
July 27, 2016: International Heart Journal
Bastian Blauenburg, Andreas Mielcarek, Florian Altegoer, Christopher D Fage, Uwe Linne, Gert Bange, Mohamed A Marahiel
The biosynthesis of iron sulfur (Fe-S) clusters in Bacillus subtilis is mediated by a SUF-type gene cluster, consisting of the cysteine desulfurase SufS, the scaffold protein SufU, and the putative chaperone complex SufB/SufC/SufD. Here, we present the high-resolution crystal structure of the SufS homodimer in its product-bound state (i.e., in complex with pyrodoxal-5'-phosphate, alanine, Cys361-persulfide). By performing hydrogen/deuterium exchange (H/DX) experiments, we characterized the interaction of SufS with SufU and demonstrate that SufU induces an opening of the active site pocket of SufS...
2016: PloS One
Shota Sasagawa, Yuhei Nishimura, Shiko Okabe, Soichiro Murakami, Yoshifumi Ashikawa, Mizuki Yuge, Koki Kawaguchi, Reiko Kawase, Ryuji Okamoto, Masaaki Ito, Toshio Tanaka
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and is associated with a number of potential outcomes, including impaired diastolic function, heart failure, and sudden cardiac death. Various etiologies have been described for HCM, including pressure overload and mutations in sarcomeric and non-sarcomeric genes. However, the molecular pathogenesis of HCM remains incompletely understood. In this study, we performed comparative transcriptome analysis to identify dysregulated genes common to five mouse HCM models of differing etiology: (i) mutation of myosin heavy chain 6, (ii) mutation of tropomyosin 1, (iii) expressing human phospholamban on a null background, (iv) knockout of frataxin, and (v) transverse aortic constriction...
2016: Frontiers in Pharmacology
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