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Friedreich ataxia

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https://www.readbyqxmd.com/read/28634302/structure-of-human-fe-s-assembly-subcomplex-reveals-unexpected-cysteine-desulfurase-architecture-and-acyl-acp-isd11-interactions
#1
Seth A Cory, Jonathan G Van Vranken, Edward J Brignole, Shachin Patra, Dennis R Winge, Catherine L Drennan, Jared Rutter, David P Barondeau
In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28605995/dna-trinucleotide-gaa-repeats-in-human-genome-hint-for-disease-pathogenesis
#2
Himanshu Narayan Singh, Barbara Scheiber-Mojdehkar, Moganty R Rajeswari
Short DNA triplet repeats are generally considered to 'benign' in nature, however, it can lead to abnormal genetic features by inducing hyper expansion including mutational hotspots, unusual DNA structure etc. Thus, the expanded DNA base triplets in human genome are expected to play crucial role in disease pathogenesis. One such triplet repeat expansion of (GAA) is observed in FXN gene which is well established to cause neurological disease "Friedreich's ataxia". To explore the association of repeats in other genes if any, we performed a systematic search in the entire human genome...
June 12, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28573291/mechanisms-of-iron-and-copper-frataxin-interactions
#3
T H L Han, J M Camadro, R Santos, E Lesuisse, J M El Hage Chahine, N T Ha-Duong
Frataxin is a mitochondrial protein whose deficiency is the cause of Friedreich's ataxia, a hereditary neurodegenerative disease. This protein plays a role in iron-sulfur cluster biosynthesis, protection against oxidative stress and iron metabolism. In an attempt to provide a better understanding of the role played by metals in its metabolic functions, the mechanisms of mitochondrial metal binding to frataxin in vitro have been investigated. A purified recombinant yeast frataxin homolog Yfh1 binds two Cu(ii) ions with a Kd1(Cu(II)) of 1...
June 2, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28562313/friedreich-s-ataxia-induced-pluripotent-stem-cell-derived-cardiomyocytes-display-electrophysiological-abnormalities-and-calcium-handling-deficiency
#4
Duncan E Crombie, Claire L Curl, Antonia Ja Raaijmakers, Priyadharshini Sivakumaran, Tejal Kulkarni, Raymond Cb Wong, Itsunari Minami, Marguerite V Evans-Galea, Shiang Y Lim, Lea Delbridge, Louise A Corben, Mirella Dottori, Norio Nakatsuji, Ian A Trounce, Alex W Hewitt, Martin B Delatycki, Martin F Pera, Alice Pébay
We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes...
May 30, 2017: Aging
https://www.readbyqxmd.com/read/28556242/cerebral-compensation-during-motor-function-in-friedreich-ataxia-the-image-frda-study
#5
Ian H Harding, Louise A Corben, Martin B Delatycki, Monique R Stagnitti, Elsdon Storey, Gary F Egan, Nellie Georgiou-Karistianis
BACKGROUND: Friedreich ataxia is characterized by progressive motor incoordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear. METHODS: In this cross-sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self-paced single-finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior...
May 27, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28543952/structural-signature-of-classical-versus-late-onset-friedreich-s-ataxia-by-multimodality-brain-mri
#6
Thiago Junqueira R Rezende, Alberto Rolim M Martinez, Ingrid Faber, Karen Girotto, José Luiz Pedroso, Orlando G Barsottini, Iscia Lopes-Cendes, Fernando Cendes, Andreia V Faria, Marcondes C França
INTRODUCTION: Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA. METHODS: We enrolled 36 patients (13 with LOFA) and 29 healthy controls...
May 23, 2017: Human Brain Mapping
https://www.readbyqxmd.com/read/28542596/progressive-mitochondrial-protein-lysine-acetylation-and-heart-failure-in-a-model-of-friedreich-s-ataxia-cardiomyopathy
#7
Amanda R Stram, Gregory R Wagner, Brian D Fogler, P Melanie Pride, Matthew D Hirschey, R Mark Payne
INTRODUCTION: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury...
2017: PloS One
https://www.readbyqxmd.com/read/28504123/erythropoietin-and-small-molecule-agonists-of-the-tissue-protective-erythropoietin-receptor-increase-fxn-expression-in-neuronal-cells-in%C3%A2-vitro-and-in-fxn-deficient-kiko-mice-in%C3%A2-vivo
#8
James L Miller, Myriam Rai, Normand L Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R Spencer
Friedreich's ataxia (FA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo...
May 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28477351/normalization-of-timed-neuropsychological-tests-with-the-pata-rate-and-nine-hole-pegboard-tests
#9
Francesco Saccà, Teresa Costabile, Filomena Abate, Agnese Liguori, Francesca Paciello, Chiara Pane, Anna De Rosa, Fiore Manganelli, Giuseppe De Michele, Alessandro Filla
INTRODUCTION: Despite neurological patients show frequent physical impairment, timed neuropsychological tests do not take this into account during scoring procedures. OBJECTIVE: We propose a normalization method based on the PATA Rate Task (PRT) and on the nine-hole pegboard test (9HPT) as a measure of dysarthria and upper limb dysfunction. METHODS: We tested 65 healthy controls on timed neuropsychological tests (Attentional Matrices [AM], Trail Making Test, Symbol Digit Modalities Test, Verbal Fluencies) to determine the time spent on phonation or on hand movement during test execution...
May 6, 2017: Journal of Neuropsychology
https://www.readbyqxmd.com/read/28474131/dysphagia-in-friedreich-ataxia
#10
Megan J Keage, Martin B Delatycki, Isabelle Gupta, Louise A Corben, Adam P Vogel
The objective of the study was to comprehensively characterise dysphagia in Friedreich ataxia (FRDA) and identify predictors of penetration/aspiration during swallowing. We also investigated the psychosocial impact of dysphagia on individuals with FRDA. Sixty participants with FRDA were screened for dysphagia using a swallowing quality of life questionnaire (Swal-QOL) and case history. Individuals reporting dysphagia underwent a standardised oromotor assessment (Frenchay Dysarthria Assessment, 2, FDA-2) and videofluoroscopic study of swallowing (VFSS)...
May 4, 2017: Dysphagia
https://www.readbyqxmd.com/read/28456899/mesenchymal-stem-cell-derived-factors-restore-function-to-human-frataxin-deficient-cells
#11
Kevin Kemp, Rimi Dey, Amelia Cook, Neil Scolding, Alastair Wilkins
Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia...
April 29, 2017: Cerebellum
https://www.readbyqxmd.com/read/28451558/comparison-of-two-different-pcr-based-methods-for-detection-of-gaa-expansions-in-frataxin-gene
#12
Mona Entezam, Akbar Amirfiroozi, Mansoureh Togha, Mohammad Keramatipour
BACKGROUND: Expansion of GAA trinucleotide repeats is the molecular basis of Friedreich's ataxia (FRDA). Precise detection of the GAA expansion repeat in frataxin gene has always been a challenge. Different molecular methods have been suggested for detection of GAA expansion, including; short-PCR, long-PCR, Triplet repeat primed-PCR (TP-PCR) and southern blotting. The aim of study was to evaluate two PCR-based methods, TP-PCR and long-PCR, and to explore the use of TP-PCR accompanying with long-PCR for accurate genotyping of FRDA patients...
February 2017: Iranian Journal of Public Health
https://www.readbyqxmd.com/read/28444186/frataxin-deficiency-impairs-mitochondrial-biogenesis-in-cells-mice-and-humans
#13
Mittal J Jasoliya, Marissa Z McMackin, Chelsea K Henderson, Susan L Perlman, Gino A Cortopassi
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here we investigated the consequences of FXN deficiency in patient derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from FRDA patients. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28412459/no-changes-in-heme-synthesis-in-human-friedreich%C3%A2-s-ataxia-erythroid-progenitor-cells
#14
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...
July 20, 2017: Gene
https://www.readbyqxmd.com/read/28411441/longitudinal-gait-and-balance-decline-in-friedreich-s-ataxia-a-pilot-study
#15
Theresa A Zesiewicz, Jeannie B Stephenson, Seok Hun Kim, Kelly L Sullivan, Israt Jahan, Yangxin Huang, Jason L Salemi, Lynn Wecker, Jessica D Shaw, Clifton L Gooch
INTRODUCTION: Friedreich's Ataxia (FA) is a devastating, progressive, neurodegenerative disease. Objective measures that detect changes in neurological function in FA patients are needed to facilitate therapeutic clinical trials. The purpose of this pilot study was to analyze longitudinal changes in gait and balance in subjects with FA using the GAITRite Walkway System(®) and Biodex Balance System™, respectively, and to test the ability of these measures to detect change over time compared to the Friedreich's Ataxia Rating Scale (FARS)...
March 30, 2017: Gait & Posture
https://www.readbyqxmd.com/read/28405347/friedreich-ataxia-current-status-and-future-prospects
#16
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/28360782/determination-of-genotypic-and-phenotypic-characteristics-of-friedreich-s-ataxia-and-autosomal-dominant-spinocerebellar-ataxia-types-1-2-3-and-6
#17
Pınar Bengi Boz, Filiz Koç, Sabriye Kocatürk Sel, Ali İrfan Güzel, Halil Kasap
INTRODUCTION: This study aimed to analyze the genotypic characteristics of Friedreich's ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings. METHODS: The study included 129 indexed cases, who applied to the neurology department and were diagnosed with hereditary cerebellar ataxia through clinical, laboratory, and electrophysiological findings, and 15 sibling patients who were diagnosed through family scanning (144 cases in total); their genetic analyses were also performed...
June 2016: Noro Psikiyatri Arsivi
https://www.readbyqxmd.com/read/28344481/stability-of-erythropoietin-repackaging-in-polypropylene-syringes-for-clinical-use
#18
Angela Marsili, Giorgia Puorro, Chiara Pane, Anna de Rosa, Giovanni Defazio, Carlo Casali, Antonio Cittadini, Giuseppe de Michele, Brunello Ettore Florio, Alessandro Filla, Francesco Saccà
Introduction: Epoetin alfa (Eprex®) is a subcutaneous, injectable formulation of short half-life recombinant human erythropoietin (rHuEPO). To current knowledge there are no published studies regarding the stability of rHuEPO once repackaging occurs (r-EPO) for clinical trial purposes. Materials and methods: We assessed EPO concentration in Eprex® and r-EPO syringes at 0, 60, 90, and 120 days after repackaging in polypropylene syringes. R-EPO was administered to 56 patients taking part in a clinical trial in Friedreich Ataxia...
February 2017: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
https://www.readbyqxmd.com/read/28286293/a-role-for-astrocytes-in-cerebellar-deficits-in-frataxin-deficiency-protection-by-insulin-like-growth-factor-i
#19
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
#20
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
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