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https://www.readbyqxmd.com/read/28812047/selected-missense-mutations-impair-frataxin-processing-in-friedreich-ataxia
#1
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/28803513/mechanisms-of-unexpected-death-and-autopsy-findings-in-friedreich-ataxia
#2
Roger W Byard, John D Gilbert
A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. The heart showed asymmetric left ventricular hypertrophy, with an interventricular septal thickness of 20-25 mm (the remainder of the left ventricular wall measured 15 mm). Histologically, both ventricles had irregular areas of marked myocyte hypertrophy with associated interstitial fibrosis and focal myofibre disarray. There was neuronal loss within the dentate nucleus of the cerebellum, with vacuolation and axonal loss in the dorsal columns and spinocerebellar tracts of the upper cervical spinal cord...
January 1, 2017: Medicine, Science, and the Law
https://www.readbyqxmd.com/read/28782591/mitochondrial-dysfunction-in-the-neuro-degenerative-and-cardio-degenerative-disease-friedreich-s-ataxia
#3
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/28770399/triphenylphosphonium-desferrioxamine-as-a-candidate-mitochondrial-iron-chelator
#4
Roxana Y P Alta, Hector A Vitorino, Dibakar Goswami, M Terêsa Machini, Breno P Espósito
Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment of iron overload-related neurodegenerative diseases. Triphenylphosphonium (TPP) is a delocalized lipophilic cation used to ferry molecules to mitochondria. Here we report the synthesis and characterization of the conjugate TPP-DFO as a mitochondrial iron chelator. TPP-DFO maintained both a high affinity for iron and the antioxidant activity when compared to parent DFO...
August 2, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/28724806/nicotinamide-mononucleotide-requires-sirt3-to-improve-cardiac-function-and-bioenergetics-in-a-friedreich-s-ataxia-cardiomyopathy-model
#5
Angelical S Martin, Dennis M Abraham, Kathleen A Hershberger, Dhaval P Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J Muehlbauer, Paul A Grimsrud, Jason W Locasale, R Mark Payne, Matthew D Hirschey
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO)...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724340/pharmacological-therapeutics-in-friedreich-ataxia-the-present-state
#6
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 20, 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/28716278/single-step-blood-direct-pcr-a-robust-and-rapid-method-to-diagnose-triplet-repeat-disorders
#7
Inder Singh, Vishnu Swarup, Sunil Shakya, Vinay Goyal, Mohammed Faruq, Achal Kumar Srivastava
OBJECTIVE: DNA extraction prior to polymerase chain reaction (PCR) amplification in genetic diagnoses of triplet repeat disorders (TRDs) is tedious and labour-intensive and has the limitations of sample contamination with foreign DNA, including that from preceding samples. Therefore, we aimed to develop a rapid, robust, and cost-effective method for expeditious genetic investigation of TRDs from whole blood as a DNA template. METHODS: Peripheral blood samples were collected from 70 clinically suspected patients of progressive ataxia...
August 15, 2017: Journal of the Neurological Sciences
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
#8
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/28695363/how-does-performance-of-the-friedreich-ataxia-functional-composite-compare-to-rating-scales
#9
Geneieve Tai, Eppie M Yiu, Martin B Delatycki, Louise A Corben
Progression of Friedreich ataxia (FRDA) is often measured using neurological rating scales such as the Friedreich Ataxia Rating Scale (FARS). Performance scales comprising functional measures have been used in other conditions due to their increased sensitivity and reproducibility and may replace examination-based measures. The aims of this study were to examine the relationship between the Friedreich Ataxia Functional Composite (FAFC) measures and characteristics of FRDA to determine if the FAFC is more sensitive to clinical change over time compared to its components...
August 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28664160/new-techniques-for-ancient-proteins-direct-coupling-analysis-applied-on-proteins-involved-in-iron-sulfur-cluster-biogenesis
#10
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/28634302/structure-of-human-fe-s-assembly-subcomplex-reveals-unexpected-cysteine-desulfurase-architecture-and-acyl-acp-isd11-interactions
#11
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
https://www.readbyqxmd.com/read/28605995/dna-trinucleotide-gaa-repeats-in-human-genome-hint-for-disease-pathogenesis
#12
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
#13
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...
August 16, 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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