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https://www.readbyqxmd.com/read/29053830/friedreich-s-ataxia-clinical-features-pathogenesis-and-management
#1
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
#2
(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
#3
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
#4
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
#5
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-s-ataxia-an-impaired-nrf2-response-mediated-via-up-regulation-of-keap1-and-activation-of-the-gsk3%C3%AE-axis
#6
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 anti-oxidant response. However, studies in models of Friedreich's ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due 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, while skeletal muscle was asymptomatic...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28931050/saxs-and-stability-studies-of-iron-induced-oligomers-of-bacterial-frataxin-cyay
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28887512/lna-effects-on-dna-binding-and-conformation-from-single-strand-to-duplex-and-triplex-structures
#10
Y Vladimir Pabon-Martinez, You Xu, Alessandra Villa, Karin E Lundin, Sylvain Geny, Chi-Hung Nguyen, Erik B Pedersen, Per T Jørgensen, Jesper Wengel, Lennart Nilsson, C I Edvard Smith, Rula Zain
The anti-gene strategy is based on sequence-specific recognition of double-strand DNA by triplex forming (TFOs) or DNA strand invading oligonucleotides to modulate gene expression. To be efficient, the oligonucleotides (ONs) should target DNA selectively, with high affinity. Here we combined hybridization analysis and electrophoretic mobility shift assay with molecular dynamics (MD) simulations to better understand the underlying structural features of modified ONs in stabilizing duplex- and triplex structures...
September 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28882199/defining-the-architecture-of-the-core-machinery-for-the-assembly-of-fe-s-clusters-in-human-mitochondria
#11
Oleksandr Gakh, Wasantha Ranatunga, Belinda K Galeano, Douglas S Smith, James R Thompson, Grazia Isaya
Although Fe-S clusters may assemble spontaneously from elemental iron and sulfur in protein-free systems, the potential toxicity of free Fe(2+), Fe(3+), and S(2-) ions in aerobic environments underscores the requirement for specialized proteins to oversee the safe assembly of Fe-S clusters in living cells. Prokaryotes first developed multiprotein systems for Fe-S cluster assembly, from which mitochondria later derived their own system and became the main Fe-S cluster suppliers for eukaryotic cells. Early studies in yeast and human mitochondria indicated that Fe-S cluster assembly in eukaryotes is centered around highly conserved Fe-S proteins (human ISCU) that serve as scaffolds upon which new Fe-S clusters are assembled from (i) elemental sulfur, provided by a pyridoxal phosphate-dependent cysteine desulfurase (human NFS1) and its stabilizing-binding partner (human ISD11), and (ii) elemental iron, provided by an iron-binding protein of the frataxin family (human FXN)...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28852135/peptide-ss-31-upregulates-frataxin-expression-and-improves-the-quality-of-mitochondria-implications-in-the-treatment-of-friedreich-ataxia
#12
Hongting Zhao, Huihui Li, Shuangying Hao, Jiping Chen, Jing Wu, Chuanhui Song, Meng Zhang, Tong Qiao, Kuanyu Li
Friedreich ataxia is a progressive neurodegenerative disease caused by the expansion of GAA trinucleotide repeats within the first intron of the FXN gene, which encodes frataxin. The pathophysiology of the disease is thought to be derived from the decrease of Fe-S cluster biogenesis due to frataxin deficiency. There is currently no effective treatment for the disease. In our study, we demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28838288/overexpression-of-drosophila-frataxin-triggers-cell-death-in-an-iron-dependent-manner
#13
Oliver Edenharter, Janik Clement, Stephan Schneuwly, Juan A Navarro
Friedreich ataxia (FRDA) is the most important autosomal recessive ataxia in the Caucasian population. FRDA patients display severe neurological and cardiac symptoms that reflect a strong cellular and axonal degeneration. FRDA is caused by a loss of function of the mitochondrial protein frataxin which impairs the biosynthesis of iron-sulfur clusters and in turn the catalytic activity of several enzymes in the Krebs cycle and the respiratory chain leading to a diminished energy production. Although FRDA is due to frataxin depletion, overexpression might also be very helpful to better understand cellular functions of frataxin...
August 24, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/28812047/selected-missense-mutations-impair-frataxin-processing-in-friedreich-ataxia
#14
Elisia Clark, Jill S Butler, Charles J Isaacs, Marek Napierala, David R Lynch
OBJECTIVE: Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. METHODS: Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing...
August 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28782591/mitochondrial-dysfunction-in-the-neuro-degenerative-and-cardio-degenerative-disease-friedreich-s-ataxia
#15
REVIEW
Shannon Chiang, Danuta S Kalinowski, Patric J Jansson, Des R Richardson, Michael L-H Huang
Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism...
August 4, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28724340/pharmacological-therapeutics-in-friedreich-ataxia-the-present-state
#16
Cassandra Strawser, Kimberly Schadt, Lauren Hauser, Ashley McCormick, McKenzie Wells, Jane Larkindale, Hong Lin, David R Lynch
Friedreich ataxia (FRDA) is a progressive, inherited, neurodegenerative disease for which there is currently no cure or approved treatment. FRDA is caused by deficits in the production and expression of frataxin, a protein found in the mitochondria that is most likely responsible for regulating iron-sulfur cluster enzymes within the cell. A decrease in frataxin causes dysfunction of adenosine triphosphate synthesis, accumulation of mitochondrial iron, and other events leading to downstream cellular dysfunction...
July 26, 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/28701783/circulating-mir-323-3p-is-a-biomarker-for-cardiomyopathy-and-an-indicator-of-phenotypic-variability-in-friedreich-s-ataxia-patients
#17
M Seco-Cervera, D González-Rodríguez, J S Ibáñez-Cabellos, L Peiró-Chova, P González-Cabo, E García-López, J J Vílchez, I Sanz-Gallego, F V Pallardó, J L García-Giménez
MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich's ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich's ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28664160/new-techniques-for-ancient-proteins-direct-coupling-analysis-applied-on-proteins-involved-in-iron-sulfur-cluster-biogenesis
#18
Marco Fantini, Duccio Malinverni, Paolo De Los Rios, Annalisa Pastore
Direct coupling analysis (DCA) is a powerful statistical inference tool used to study protein evolution. It was introduced to predict protein folds and protein-protein interactions, and has also been applied to the prediction of entire interactomes. Here, we have used it to analyze three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that DCA can correctly reproduce structural features of the CyaY/frataxin family (a protein involved in the human disease Friedreich's ataxia) despite being based on the relatively small number of sequences allowed by its genomic distribution...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28640740/differential-effects-of-isc-operon-mutations-on-the-biosynthesis-and-activity-of-key-anaerobic-metalloenzymes-in-escherichia-coli
#19
Monique Jaroschinsky, Constanze Pinske, R Gary Sawers
Escherichia coli has two machineries for the synthesis of FeS clusters, namely Isc (iron-sulfur cluster) and Suf (sulfur formation). The Isc machinery, encoded by the iscRSUA-hscBA-fdx-iscXoperon, plays a crucial role in the biogenesis of FeS clusters for the oxidoreductases of aerobic metabolism. Less is known, however, about the role of ISC in the maturation of key multi-subunit metalloenzymes of anaerobic metabolism. Here, we determined the contribution of each iscoperon gene product towards the functionality of the major anaerobic oxidoreductases in E...
June 22, 2017: Microbiology
https://www.readbyqxmd.com/read/28634302/structure-of-human-fe-s-assembly-subcomplex-reveals-unexpected-cysteine-desulfurase-architecture-and-acyl-acp-isd11-interactions
#20
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...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
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