(WO/2010/083327) MEASURING LEVELS OF FRATAXIN

PATENT, WO/2010/083327, PCT/US2010/021067

MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH (US), OGLESBEE, Devin; (US),
MATERN, Dietrich; (US), ISAYA, Grazia; (US).

A method for assessing levels of a frataxin polypeptide in a mammal.

This document relates to methods and materials involved in measuring levels of a frataxin polypeptide present in a biological sample. For example, methods and materials related to the use of anti-frataxin antibody-bound microspheres and biotinylated anti-frataxin antibodies to measure the levels of a frataxin polypeptide in a biological sample from a mammal (e.g., a newborn human) are provided.

Co-precipitation of phosphate and iron limits mitochondrial phosphate availability in Saccharomyces cerevisiae lacking the yeast frataxin homologue (YFH1)

J. Biol. Chem. jbc.M110.163253First Published on December 28, 2010, doi:10.1074/jbc.M110.163253

Alexandra Seguin, Renata Santos, Debkumar Pain, Andrew Dancis, Jean-Michel Camadro, Emmanuel Lesuisse

Institut Jacques Monod, France; University of Medicine and Dentistry of New Jersey, United States; University of Pennsylvania, United States

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Enfermedad cardiovascular en pacientes cubanos afectados por Ataxia de Friedreich.

Cardiovascular disease in Cuban patients affected by Friedreich's ataxia. (full text in Spanish)

Revista Electrónica "Ciencias Holguín", Año XVI, No. 4, Mes Diciembre 2010, ISSN 1027-2127.

Dra. Tania Cruz Mariño. Dra. Ana Luz Portelles Caminero. Dr. William Áreas Zalazar. Dr. Luis Velázquez Pérez.

ABSTRACT

In describing the Friedreich's ataxia, Nicholaus referred to cardiac disease. This autosomal recessive disease is due to dynamic mutation in the FRDA gene, encoding the protein frataxin deficiency, leading to oxidative stress and cardiac cell death. This research was conducted in order to describe the cardiovascular abnormalities present in Cuban patients affected by Friedreich's ataxia. Individuals with confirmatory molecular diagnosis of the disease underwent electrocardiogram, echocardiogram, and clinical assessment by internationally validated scales: ICARS and SARA. Ventricular re-polarization disorders diffuse intra-atrial conduction disturbances and disorders of diastolic function were common findings. The restrictive pattern appreciated provides live evidence that the disease leads to left ventricular diastolic dysfunction. The occurrence of a silent acute myocardial infarction indicates the importance of identifying emerging forms of myocardial involvement.

KEY WORDS: FRIEDREICH'S ATAXIA; HEREDITARY ATAXIA; CARDIOMYOPATHY; MYOCARDIAL INFARCTION.

Generation of Induced Pluripotent Stem Cell Lines from Friedreich Ataxia Patients.

Stem Cell Rev. 2010 Dec 22.

Liu J, Verma PJ, Evans-Galea MV, Delatycki MB, Michalska A, Leung J, Crombie D, Sarsero JP, Williamson R, Dottori M, Pébay A.

Centre for Reproduction and Development, Monash Institute of Medical Research, Monash University, Melbourne, Australia,

Keywords: Friedreich ataxia (FRDA), neurodegeneration, cardiomyopathy, trinucleotide (GAA) repeat expansion, FXN gene, frataxin, induced pluripotent stem (iPS) cell lines, skin fibroblasts, pluripotent, peripheral neurons, cardiomyocytes, models, human BAC, immunocompatible cells, transplantation therapy.

PREIMPLANTATION GENETIC DIAGNOSIS (PGD)

Important Info: Although it is a private center information, explains very well the technique, in layman's language ,I do not try in any way publicize the medical center.

PREIMPLANTATION GENETIC DIAGNOSIS (PGD) Patient Information

Some couples are at risk of transmitting an inherited disease to their children. One of the couple may be affected by this disease, or they each may carry a mutation, which if both were inherited by a child would cause the disease. Preimplantation genetic diagnosis (PGD) is a way of detecting a specific disease-causing genetic mutation within an embryo before it is transferred to the womb and forms a pregnancy.

Rare diseases, orphan drugs and their regulation: questions and misconceptions

Nature Reviews Drug Discovery 9, 921-929 (December 2010) | doi:10.1038/nrd3275

Erik Tambuyzer

Sustained advocacy efforts driven by patients' organizations to make rare diseases a health priority have led to regulatory and economic incentives for .....

Iron-dependent functions of mitochondria-relation to neurodegeneration.

J Neural Transm. 2010 Dec 15.
Gille G, Reichmann H.
Klinik und Poliklinik für Neurologie, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany

Keywords: neurodegenerative diseases, iron dyshomeostasis, mitochondrial dysfunction, physiological role of iron in mitochondria, Friedreich ataxia (FRDA),idiopathic Parkinson disease (PD), respiratory chain, iron-sulphur clusters, cytochromes, aconitase, frataxin gene, frataxin, reactive oxygen species.

Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome.

Eur Heart J. 2010 Dec 14. [Epub ahead of print]

Raman SV, Phatak K, Hoyle JC, Pennell ML, McCarthy B, Tran T, Prior TW, Olesik JW, Lutton A, Rankin C, Kissel JT, Al-Dahhak R.
The Ohio State University, 473 W. 12th Ave, Suite 200, Columbus, OH 43210, USA.

Keywords: Cardiomyopathy, Friedreich ataxia (FA), fibrosis, cardiac magnetic resonance with adenosine, precontrast imaging, myocardial iron estimation, myocardial perfusion reserve index (MPRI), left ventricular (LV) mass, left ventricular ejection fraction.

Connecting Variability in Global Transcription Rate to Mitochondrial Variability

PLOS Biology, Dec 14, 2010 (publication date)

Ricardo Pires das Neves1,2,3, Nick S. Jones4, Lorena Andreu1, Rajeev Gupta1, Tariq Enver1, Francisco J. Iborra1,5*

1 Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom, 2 Biocant Center of Innovation and Biotechnology, Cantanhede, Portugal, 3 Center for Neuroscience and Cell Biology University of Coimbra, Coimbra, Portugal, 4 Department of Physics and Biochemistry, Oxford Centre for Integrative Systems Biology, CABDyN Complexity Centre, Oxford, United Kingdom, 5 Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain

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A Decrementing Form of Plasticity Apparent in Cerebellar Learning

The Journal of Neuroscience, December 15, 2010, 30(50):16993-17003; doi:10.1523/JNEUROSCI.2455-10.2010

Tatsuya Ohyama,1 Horatiu Voicu,3 Brian Kalmbach,1 and Michael D. Mauk1,2

1Center for Learning and Memory and 2Section of Neurobiology, The University of Texas at Austin, Austin, Texas 78712-0805, and 3Department of Neurobiology and Anatomy, The University of Texas-Houston Health Science Center, Houston, Texas 77030

" These results demonstrate the utility of eyelid conditioning as a means to identify and characterize the rules that govern input to output transformations in the cerebellum."

The value of Arabidopsis research in understanding human disease states.

Curr Opin Biotechnol. 2010 Dec 6.

Xu XM, Møller SG.
Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Norway.

Keywords: Arabidopsis thaliana, understand molecular mechanisms, human disease, neurodegenerative disorders, Alzheimer's, Parkinson's, Friedreich Ataxia.

Blood cells from Friedreich ataxia patients harbor frataxin deficiency without a loss of mitochondrial function

Mitochondrion, Article in Press, Accepted Manuscript, doi:10.1016/j.mito.2010.12.003

Mary A. Selak a, Elise Lyver b, Elizabeth Micklow b, Eric C. Deutsch c, Ozlem Onder d, Nur Selamoglu d, Claire Yager a, Simon Knight b, Martin Carroll b, Fevzi Daldal d, Andrew Dancis b, David R. Lynch c and Jean-Emmanuel Sarry b,

a Children's Hospital of Philadelphia Research Institute, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA
b Division of Hematology/Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
c Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, and Children's Hospital of Philadelphia, Philadelphia, PA, USA
d Department of Biology, University of Pennsylvania, Philadelphia, PA, USA

KEYWORDS: Friedreich ataxia (FRDA), frataxin, neurons, cardiomyocytes, platelets, peripheral blood mononuclear cells, mitochondria, biomarkers.

Restless legs syndrome in Friedreich ataxia: A polysomnographic study

Movement Disorders, n/a. doi: 10.1002/mds.22769 (Early View (Articles online in advance of print)
Frauscher, B., Hering, S., Högl, B., Gschliesser, V., Ulmer, H., Poewe, W. and Boesch, S. M.

Keywords: sleep disturbance, restless legs syndrome, Friedreich ataxia, Frataxin, ferritin, periodic leg movements, polysomnography.

US reviews human trial participant protections

The Lancet, Volume 376, Issue 9757, Pages 1975 - 1976, 11 December 2010, doi:10.1016/S0140-6736(10)62247-7

Nellie Bristol

Commission Chair Amy Gutmann, President of the University of Pennsylvania stated. “We have an ethical obligation to protect the health and well-being of all research participants.”

Electrophysiology of Respiratory Chain Complexes and the ADP-ATP Exchanger in Native Mitochondrial Membranes.

Biochemistry. 2010 Dec 7;49(48):10308-18. Epub 2010 Nov 11.

Watzke N, Diekert K, Obrdlik P.
IonGate Biosciences GmbH, Industriepark Hoechst, D528, 65926 Frankfurt am Main, Germany.

Keywords: mitochondrial membranes, proton-pumping respiratory chain complexes, mitochondrial secondary active solute transport proteins, solid-supported membrane (SSM) technology, respiratory chain complexes CI, CII, CIII, and CIV, the F(O)F(1)-ATPase/synthase (CV), the adenine nucleotide translocase (ANT), oxidative phosphorylation (OXPHOS), uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), IC(50), Coenzyme Q (CoQ), decylubiquinone (DBQ), idebenone (Ide).

Axial diffusivity is increased in the degenerating superior cerebellar peduncles of Friedreich's ataxia.

Neuroradiology. 2010 Dec 3. [Epub ahead of print]

Della Nave R, Ginestroni A, Diciotti S, Salvatore E, Soricelli A, Mascalchi M., S. Giuseppe Hospital, Radiodiagnostic Section, Empoli, Italy.

Keywords: Decreased fractional anisotropy (FA), diffusion tensor MR imaging (DTI), white matter (WM), radial diffusivity, axial diffusivity, Friedreich's ataxia (FRDA), selective neuronal loss, dentate nuclei, cerebellar peduncles (SCPs), TBSS analysis.

Large-scale in silico modeling of metabolic interactions between cell types in the human brain

Nature Biotechnology, Year published:(2010), DOI: doi:10.1038/nbt.1711

Nathan E Lewis, Gunnar Schramm, Aarash Bordbar, Jan Schellenberger, Michael P Andersen, Jeffrey K Cheng, Nilam Patel, Alex Yee, Randall A Lewis, Roland Eils, Rainer König, Bernhard Ø Palsson.

Keywords: Metabolic interactions, gene expression data, proteomics data, literature-based manual curation, model human metabolism, metabolites, interstitial fluid, models of brain energy metabolism, astrocytes, Alzheimer's disease, regions of the brain.

Simplest explanation: Metabolism Models May Explain Why Alzheimer's Disease Kills Some Neuron Types First (ScienceDaily (Dec. 6, 2010)

Taking the lottery out of gene therapy

NEW SCIENTIST HEALTH ,Magazine issue 2789

GENE therapy should become a more exact science thanks to the discovery that it is possible to predict where a transferred gene is likely to be inserted into the recipient's DNA.

"Peter Cherepanov at Imperial College London, who was not part of the team, says now that the probability of an undesirable insertion can be estimated, it will become easier to balance the chance of success with the risk of side effects."

ORIGINAL PAPER: Deciphering the Code for Retroviral Integration Target Site Selection

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Catalysis and Mechanistic Insights into Sirtuin Activation.

Chembiochem. 2010 Nov 9. [Epub ahead of print]

 Dittenhafer-Reed KE, Feldman JL, Denu JM.

Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison.

Keywords:  SIRT1, resveratrol,  SRT1720, mechanism by which they activate remains poorly defined,  type II diabetes, neurodegeneration, diseases associated with aging.

Repeat expansion affects both transcription initiation and elongation in friedreich ataxia cells

J Biol Chem. 2010 Dec 2. [Epub ahead of print]

Kumari D, Biacsi RE, Usdin K., NIH, United States.

Keywords: Expansion of a GAA·TTC-repeat, first intron, frataxin (FXN) gene, mRNA deficit, Friedreich ataxia (FRDA), DNA methylation, histone modifications, chromatin immuno-precipitation, chromatin, RNA polymerase II, histone H3 trimethylated on lysine 4, trimethylated H3K36.

Accelerating orphan drug development

Nature Reviews Drug Discovery 9, 901-902 (December 2010) | doi:10.1038/nrd3340

Timothy R. Coté, Kui Xu & Anne R. Pariser

"Given the limited resources available for rare disease R&D, it is imperative that all knowledge gained is used to maximum benefit at each phase.
The FDA is committed to accelerating orphan drug development through a regulatory system built on integrity, consistency and transparency; a system that has delivered benefits to people who desperately need them and promises to deliver much more."

The Neuropathology of Late-Onset Friedreich's Ataxia.

Cerebellum. 2010 Dec 4. [Epub ahead of print]

Koeppen AH, Morral JA, McComb RD, Feustel PJ.
Research Service (151), VA Medical Center, 113 Holland Ave, Albany, NY, 12208, USA.

Keywords: Friedreich's ataxia (FRDA), very young persons, routine laboratory test, cardiomyopathy, late-onset, neurological disability, dorsal root ganglia, atrophy of the dentate nucleus, Frataxin levels.

Mitochondrial Fe-S cluster biogenesis, frataxin and the modulation of susceptibility to drug-induced cardiomyopathy

Aging (Albany NY). 2010 Nov 27.
Michael N. Sack
NHLBI Center for Molecular Medicine, National Institutes of Health, Bethesda, MD 20892, USA
Commentary on: Schulz et al. Activation of mitochondrial energy metabolism protects against cardiac failure. Aging 2010; 2: this issue

OPEN ACCESS

An intriguing new finding, by Shultz et al is published in AGING regarding the induction of frataxin. Mutations in frataxin result in the development of Friedreich's Ataxia, an inherited neurodegenerative disease associated with the development of severe cardiomyopathy. Frataxin, itself is involved in mitochondrial iron-sulphur cluster biogenesis which functions, in part, to incorporate appropriate amounts of iron into mitochondrial proteins including aconitase and succinate dehydrogenase [13]. Whether frataxin functions as an iron-chaperone protein or plays a regulatory role in controlling iron and sulphur flux within mitochondria is not yet completely characterized. Nevertheless, the study by Shultz and colleagues [14] shows that increased cardiac frataxin enhances tricarboxylic acid cycle function resulting in increased cardiac ATP, NADH, NADPH and reduced glutathione levels. This array of features is consistent with an enhanced bioenergetic capacity and increased antioxidant defenses. The authors go on to demonstrate that overexpression of frataxin is cardioprotective against doxorubicin-induced cardiomyopathy. This intriguing study shows that the modulation of the mitochondria at the fundamental level of integrating cofactors required for protein functional integrity have beneficial effects in disease processes that are exacerbated by mitochondrial dysfunction. This study further highlights the complexity of mitochondrial function and adds a new level of regulation operational in the pathophysiology of heart failure that may be amenable to therapeutic modulation.

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The mitochondrial protein frataxin is essential for heme biosynthesis in plants

FEBS Journal, Accepted Article (Accepted, unedited articles published online for future issues)
DOI: 10.1111/j.1742-4658.2010.07968.x

María V. Maliandi1, Maria V. Busi2, Valeria R. Turowski2, Laura Leaden2, Alejandro Araya3, Diego F. Gomez-Casati2.

# 1 Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH) CONICET/UNSAM, Chascomús, Argentina.# 2 Centro de Estudios Fotosintéticos y Bioquímicos (CEFOBI-CONICET), Universidad Nacional de Rosario, Rosario, Argentina. # 3 Microbiologie Cellulaire et Moléculaire et Pathogénicité.Centre National de la Recherche Scientifique and Université Victor Segalen-Bordeaux 2, Bordeaux, France.

Keywords: Frataxin, mitochondrial protein, cellular iron homeostasis, Fe–S cluster, heme biosynthesis, photosynthetic organisms, aconitase, succinate dehydrogenase, AtFH. heme content.

Superior Cerebellar Peduncle Atrophy in Friedreich's Ataxia Correlates with Disease Symptoms.

Cerebellum. 2010 Nov 24.

Akhlaghi H, Corben L, Georgiou-Karistianis N, Bradshaw J, Storey E, Delatycki MB, Egan GF.
Florey Neurosciences Institute, Centre for Neurosciences, University of Melbourne, Parkville, VIC, Australia

KEYWORDS: Friedreich's ataxia (FRDA), cerebellar-sensory ataxia, peripheral sensory loss, loss of lower limb tendon reflexes, hypertrophic cardiomyopathy, superior cerebellar peduncle (SCP), Friedreich's ataxia rating scale score, surrogate marker of disease severity in FRDA.

Feasibility of Implantable Cardioverter Defibrillator Treatment in Five Patients With Familial Friedreich's Ataxia—A Case Series

Artificial Organs, Volume 34, Issue 11, pages 1061–1065, November 2010, DOI: 10.1111/j.1525-1594.2010.01140.x

Keywords: Friedreich's ataxia (FRA), familial cardiomyopathy, the most common cause of death, implantable cardioverter defibrillator (ICD), University Hospital of Goettingen, frataxin locus, electrocardiogram, ventricular dysfunction, ventricular tachyarrhythmias.

"Our experience implies the safe use of ICD in children with FRA"

The future of genetic research on neurodegeneration

Nature Medicine 16, 1215 - 1217 (2010), doi:10.1038/nm.2225


Christine Van Broeckhoven is at the Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, and the Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

Les ataxies cérébelleuses autosomiques récessives

Original article in French, abstract in English Autosomal recessive cerebellar ataxias

Revue Neurologique, Article in Press, Corrected Proof
doi:10.1016/j.neurol.2010.07.021

M. Anheim, Service de neurogénétique, hôpital de la Pitié-Salpêtrière, Paris, France, Centre de référence des maladies neurogénétiques de l’enfant et de l’adulte, Paris, France, Unité Inserm UMR_S975 CRICM, hôpital de la Pitié-Salpêtrière, Paris, France

Keywords: Ataxia; Cerebellum; Autosomal recessive; Oculomotor apraxia; Peripheral neuropathy; Friedreich's ataxia

METHODS OF IDENTIFYING HISTONE DEACETYLASE INHIBITORS USEFUL FOR NEUROLOGICAL DISORDERS

United States Patent Application 20100285476

Inventors:Rusche, James R. (Senior Vice President of Research & Development, Repligen Corporation)
Cooper, Andrew (Senior Research Scientist at Repligen Corporation)

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Activation of mitochondrial energy metabolism protects against cardiac failure.

Aging (Albany NY). 2010 Nov 16.

Schulz TJ, Westermann D, Isken F, Voigt A, Laube B, Thierbach R, Kuhlow D, Zurse K, Schomburg L, Pfeiffer AF, Tschöpe C, Ristow M.
Department of Human Nutrition, Institute of Nutrition, University of Jena, Germany.

Keywords: Cardiac failure, impaired energy homeostasis in the heart, Mitochondrial metabolism, over-expressing the mitochondrial protein frataxin, iron-sulfur-cluster biogenesis, mitochondrial electron flux, stress defense mechanisms, cardiomyopathy, insulin/IGF-1 signaling cascade, protein kinase B, Akt, glycogen synthase kinase 3.

The Test of Everyday Attention Reveals Significant Sustained Volitional Attention and Working Memory Deficits in Friedreich Ataxia.

J Int Neuropsychol Soc. 2010 Nov 17:1-5. [Epub ahead of print]

Klopper F, Delatycki MB, Corben LA, Bradshaw JL, Rance G, Georgiou-Karistianis N.
Experimental Neuropsychology Research Unit, School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia.

Keywords: Sustained volitional attention, working memory capacity, Friedreich ataxia (FRDA), Test of Everyday Attention, IQ-matched controls, GAA repeat number, FXN gene, disease severity, corticocerebellar pathways, cortical and/or cerebellar pathology.

Development and assessment of selective mitochondrion-targeted iron chelators for the study of the neurological disorder Friedrich’s Ataxia

Department of Pharmacy & Pharmacology, University of Bath

NEW PROJECT

"we will investigate the conjugation of a variety of clinical strong iron chelator molecules to cell-penetrating and mitochondria-targeting peptide sequences, to create highly specific cell-permeable metal chelators"

Development of Biomarkers for HDAC Inhibitor Treatment of Friedreich's Ataxia

AAN 2010 - American Academy of Neurology

Massimo Pandolfo, Brussels, Belgium, Heather Plasterer, Waltham, MA, Myriam Rai, Brussels, Belgium, Sushil Sharma, Carly Therkelsen, Andrew Cooper, Waltham, MA, Jennifer Farmer, David Lynch, Philadelphia, PA, James Rusche, Waltham, MA

Effects of Erythropoietin on Endothelial Progenitor Cells, Frataxin Levels and Oxidative Metabolism in the Skeletal Muscle of Friedreich Ataxia Patients

AAN 2010 - American Academy of Neurology?

Wolfgang Nachbauer, Julia Wanschitz, Markus Reindl, Innsbruck, Austria, Barbara Scheiber-Mojdehkar, Vienna, Austria, Werner Poewe, Sylvia Boesch, Innsbruck, Austria

STATegics, Inc. Announces Award from the Department of Defense to Advance Proprietary Small Molecule Mimetics of Erythropoietin for the Treatment of Traumatic Brain Injury

SUNNYVALE, Calif., Nov. 16, 2010 (GLOBE NEWSWIRE)
STATegics' programs have been supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), Friedreich's Ataxia Research Alliance (FARA) and the U.S. Government's Qualifying Therapeutic Discovery Project (QTDP) program.

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The lead indication for the erythropoietin mimetics is Friedreich's ataxia,
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Whole-body vibration alters blood flow velocity and neuromuscular activity in Friedreich’s ataxia

Clinical Physiology and Functional Imaging, no. doi: 10.1111/j.1475-097X.2010.00992.x
Herrero, A. J., Martín, J., Martín, T., García-López, D., Garatachea, N., Jiménez, B. and Marín, P. J.

Keywords: Doppler ultrasound, electromyography, oscillating platform, rate of perceived exertion, rehabilitation, vibration frequency.

Re-Engineering Erythropoietin as an IgG Fusion Protein That Penetrates the Blood−Brain Barrier in the Mouse

Mol. Pharmaceutics, Article ASAP, DOI: 10.1021/mp1001763

 

Qing-Hui Zhou^†, Ruben J. Boado^†‡, Jeff Zhiqiang Lu^‡, Eric Ka-Wai Hui^‡, and William M. Pardridge*^†

Department of Medicine, UCLA, Los Angeles, California 90024, United States, and ArmaGen Technologies, Inc., Santa Monica, California 90401, United States

 

Keywords: drug targeting; drug delivery; Erythropoietin (EPO),  neuroprotective agent,  blood−brain barrier (BBB), chimeric monoclonal antibody (mAb),  transferrin receptor (TfR),  cTfRMAb-EPO, fusion protein,  IgG fusion protein,

 

DockAnalyse: an application for the analysis of protein-protein interactions

BMC Structural Biology 2010, 10:37doi:10.1186/1472-6807-10-37

Isaac Amela , Pedro Delicado , Antonio Gomez , Silvia Bonas , Enrique Querol and Juan Cedano

Institut de Biotecnologia i de Biomedicina Parc de Recerca UAB and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona. 08193-Bellaterra, Barcelona, Spain
Departament d’Estadística i Investigació Operativa, Universitat Politècnica de Catalunya. 08034-Barcelona, Spain.

OPEN ACCESS

.../...

Most of the studies prompt the suggestion that the iron and sulfur atoms required for the ISC biogenesis on Isu1/Isu2 are donated by other proteins, named Frataxin and Nfs1 [20]. This ISC biogenesis machinery is not yet well understood and problems in it cause several human diseases linked to protein/enzyme deficits.

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Iron-Sulfur Clusters: Biogenesis, Molecular Mechanisms and Their Functional Significance

Iron-Sulfur Clusters: Biogenesis, Molecular Mechanisms and Their Functional Significance

Xiang Ming Xu, Simon Geir Møller. Antioxidants & Redox Signaling. -Not available-, ahead of print. doi:10.1089/ars.2010.3259.

Keywords:Iron-sulfur clusters [Fe-S], inorganic cofactors, regulation of enzyme activity, mitochondrial respiration, ribosome biogenesis, cofactor biogenesis, gene expression regulation, nucleotide metabolism, mitochondria, human diseases.

Spectral measures of the effects of Friedreich's ataxia on speech.

Int J Speech Lang Pathol. 2010 Nov 9. [Epub ahead of print]

Rosen KM, Folker JE, Murdoch BE, Vogel AP, Cahill LM, Delatycki MB, Corben LA.
The University of Queensland, Brisbane, Australia.

Keywords:Friedreich's ataxia (FRDA), speech motor control, dysarthria, ,speaking task, spectral variation.

Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit†

Saccà, F., Piro, R., De Michele, G., Acquaviva, F., Antenora, A., Carlomagno, G., Cocozza, S., Denaro, A., Guacci, A., Marsili, A., Perrotta, G., Puorro, G., Cittadini, A. and Filla, A. , Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit. Movement Disorders, n/a. doi: 10.1002/mds.23435

Tags: efficacy, safety, and tolerability, two single doses of Epoetin alfa, Friedreich's ataxia, subcutaneously, frataxin, did not affect hematocrit, cardiac function, and neurological scale, phlebotomy, lack of erythropoietic effect.

The benefits and limitations of animal models for translational research in neurodegenerative diseases

Nature Medicine 16, 1210 - 1214 (2010), doi:10.1038/nm.2224

Mathias Jucker is at the Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, and the DZNE-German Center for Neurodegenerative Diseases, Tübingen, Germany.

The Herrenhausen Symposium on Neurodegeneration

Nature Medicine 16, 1200 (2010), Published online: 4 November 2010 | doi:10.1038/nm1110-1200

Although the pathological hallmarks of neurodegenerative diseases have been described for over 100 years, our understanding of the molecular events leading to neuronal death has emerged over the past two decades. Despite all of this progress in basic research, why do we still lack disease-modifying therapeutics?

Use of botulinum toxin in the neurology clinic

Nature Reviews Neurology 6, 624-636 (November 2010) | doi:10.1038/nrneurol.2010.149

Erle C. H. Lim & Raymond C. S. Seet

Keywords: Botulinum neurotoxin (BoNT), Electromyography, endoscopy, imaging techniques, ultrasonography, fluoroscopy, mechanisms of action, neurological conditions, dystonia, spasticity, headaches,painful disorders, hemifacial spasm, essential tremor, motor tics, hyperhidrosis, sialorrhea, dosing, and methods of administration.

Differentiating Impairment Levels in Temporal Versus Spatial Aspects of Linguopalatal Contacts in Friedreich's Ataxia.

Motor Control. 2010 Oct;14(4):490-508.

Folker JE, Murdoch BE, Cahill LM, Rosen KM, Delatycki MB, Corben LA, Vogel AP.

School of Health and Rehabilitation Sciences, The University of Queensland, St Lucia, Qld,
Australia.

Keywords; Electropalatography (EPG), pattern of linguopalatal contact, consonant phase durations, dysarthria, Friedreich's ataxia (FRDA), articulatory impairment in FRDA.

Getting to the Core of Repeat Expansions by Cell Reprogramming

Cell Stem Cell, Volume 7, Issue 5, 545-546, 5 November 2010, doi:10.1016/j.stem.2010.10.005.

Sergei M. Mirkin

Keywords: iPSCS, Friedreich's ataxia, (GAA)n repeat, repeat instability, epigenetic signature.

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Scripps Research team implicates wayward DNA-repair enzyme in Friedreich's ataxia

Easy to understand explanation of this recently published paper

Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability.

Various sources:

http://www.physorg.com/news/2010-11-implicate-wayward-dna-repair-enzyme-friedreich.html

http://www.sciencecodex.com/scripps_research_team_implicates_wayward_dnarepair_enzyme_in_friedreichs_ataxia

TRPing up the genome: tandem repeat polymorphisms as dynamic sources of genetic variability in health and disease.

Discov Med. 2010 Oct;10(53):314-21.

Hannan AJ.
Howard Florey Institute, Florey Neuroscience Institutes and Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia

Keyword: Repetitive DNA sequences, tandem repeat polymorphisms (TRPs), genomic variability, post-mitotic instability, neuronal function and dysfunction, single nucleotide polymorphisms (SNPs), monogenic disorders, Huntington's disease, spinocerebellar ataxias, polyglutamine diseases, Friedreich ataxia, fragile X syndrome, myoclonic epilepsy, polyalanine disorders, myotonic dystrophy. "missing heritability".

Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability.

Cell Stem Cell. 2010 Nov 5;7(5):631-7.

Ku S, Soragni E, Campau E, Thomas EA, Altun G, Laurent LC, Loring JF, Napierala M, Gottesfeld JM.

Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Keywords: Friedreich's ataxia (FRDA), GAA⋅TTC triplet repeat, frataxin, heterochromatin-mediated gene silencing, induced pluripotent stem cells (iPSCs), fibroblasts, repeat instability, repair enzyme MSH2, shRNA silencing of MSH2.

Neuronal inactivation of PPAR{gamma} Coactivator 1{alpha}(PGC-1{alpha}) protects mice from diet-induced obesity and leads to degenerative lesions.

J Biol Chem. 2010 Oct 13. [Epub ahead of print]

Ma D, Li S, Lucas EK, Cowell RM, Lin JD.
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan;


These studies have demonstrated a physiological role for neuronal PGC-1α in the control of energy balance and strongly suggest that neuronal PGC-1α exerts profound effects on the neural circuitry that governs systemic energy balance.

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Remark: Interesting conclusions about the action of PGC1-alpha in the neurons, I would like to emphasize that the action of PGC1-a is greatly diminished in the FA.

Structural; Mechanistic and Coordination Chemistry of Relevance to the Biosynthesis of Iron-Sulfur and Related Iron Cofactors

Coordination Chemistry Reviews, doi:10.1016/j.ccr.2010.10.016

Structural; Mechanistic and Coordination Chemistry of Relevance to the Biosynthesis of Iron-Sulfur and Related Iron Cofactors

Wenbin Qi (a) and J.A. Cowan (a,b)

a Ohio State Biochemistry Program, The Ohio State University
b Department of Chemistry, The Ohio State University

Available online 28 October 2010.

Patent application title: FORMULATIONS OF TOCOTRIENOL QUINONES FOR THE TREATMENT OF OPHTHALMIC DISEASES

Inventors: William D. Shrader Viktoria Kheifets Guy M. MILLER

Publication date: 10/28/2010

.../...

14. The method according to claim 6, wherein the ocular symptoms are associated with inherited mitochondrial diseases; Chronic Progressive External Opthalmoplegia (CPEO); Spinocerebellar ataxia (SCA), also called Machado-Joseph disease; Leigh's Syndrome; Friedreich's ataxia (FRDA); Mitochondrial Myopathy, ....

.../...

Research offers clues to mechanisms behind childhood-onset disorder, Friedreich's ataxia

Wayne State University, Public Relations, October 28, 2010.

Wayne State University researcher reviews link between frataxin and iron-sulfur clusters

DETROIT - Friedreich's ataxia is a childhood-onset disorder that causes progressive sensory and muscle loss. The molecular mechanisms and processes behind the incurable disorder are still in question, but a Wayne State University researcher is getting closer to the answer.

Timothy L. Stemmler, Ph.D., associate professor of biochemistry and molecular biology in WSU's School of Medicine, has studied the causality of Friedriech's ataxia......
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Exploration of transitional life events in individuals with Friedreich ataxia: Implications for genetic counseling

Behavioral and Brain Functions 2010, 6:65doi:10.1186/1744-9081-6-65
Published: 27 October 2010

V Brook White1*, Jennifer R Leib 2, Jennifer M Farmer3, Barbara B Biesecker4
1Clinical Genetics, Carolinas Medical Center, PO Box 32861, Charlotte, NC 28232-
2861, USA
2HealthFutures, Washington, DC, USA
3Friedreich’s Ataxia Research Alliance, Exton, PA, USA
4National Human Genome Research Institute, National Institutes of Health,
Bethesda, MD, USA

OPEN ACCESS

Background

Human development is a process of change, adaptation and growth. Throughout this process, transitional events mark important points in time when one's life course is significantly altered. This study captures transitional life events brought about or altered by Friedreich ataxia, a progressive chronic illness leading to disability, and the impact of these events on an affected individual's life course.
Methods

Forty-two adults with Friedreich ataxia (18-65y) were interviewed regarding their perceptions of transitional life events. Data from the interviews were coded and analyzed thematically using an iterative process.
Results

Identified transitions were either a direct outcome of Friedreich ataxia, or a developmental event altered by having the condition. Specifically, an awareness of symptoms, fear of falling and changes in mobility status were the most salient themes from the experience of living with Friedreich ataxia. Developmental events primarily influenced by the condition were one's relationships and life's work.
Conclusions

Friedreich ataxia increased the complexity and magnitude of transitional events for study participants. Transitional events commonly represented significant loss and presented challenges to self-esteem and identity. Findings from this study help alert professionals of potentially challenging times in patients' lives, which are influenced by chronic illness or disability. Implications for developmental counseling approaches are suggested for genetic counseling.

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Research on epigenetic regulation of the CNS

Research on epigenetic regulation of the CNS is a field that is currently being studied for its implications in neuronal regulation. The following papers, although are not about FA, are interesting because they show how these advances can be very important to find a cure for the disease.


Focus on epigenetics
Nature Neuroscience 13, 1299 (2010), Published online: 26 October 2010 | doi:10.1038/nn1110-1299

Epigenetic regulation of the neural transcriptome: the meaning of the marks

Nature Neuroscience 13, 1313 - 1318 (2010), Published online: 26 October 2010 | doi:10.1038/nn1110-1313

Dynamic epigenetic regulation in neurons: enzymes, stimuli and signaling pathways

Nature Neuroscience 13, 1330 - 1337 (2010), Published online: 26 October 2010 | doi:10.1038/nn.2671

Epigenetic choreographers of neurogenesis in the adult mammalian brain
Nature Neuroscience 13, 1338 - 1344 (2010)
Published online: 26 October 2010 | doi:10.1038/nn.2672

The Nrf2 System as a Potential Target for the Development of Indirect Antioxidants

Molecules. 2010 Oct 20;15(10):7266-91.

Kyeong-Ah Jung and Mi-Kyoung Kwak * email
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 712-749, Korea

OPEN ACCESS

Abstract:
Oxidative stress causes damage to multiple cellular components such as DNA, proteins, and lipids, and is implicated in various human diseases including cancer, neurodegeneration, inflammatory diseases, and aging. In response to oxidative attack, cells have developed an antioxidant defense system to maintain cellular redox homeostasis and to protect cells from damage. The thiol-containing small molecules (e.g. glutathione), reactive oxygen species-inactivating enzymes (e.g. glutathione peroxidase), and phase 2 detoxifying enzymes (e.g. NAD(P)H: quinine oxidoreductase 1 and glutathione-S-transferases) are members of this antioxidant system. NF-E2-related factor 2 (Nrf2) is a CNC-bZIP transcription factor which regulates the basal and inducible expression of a wide array of antioxidant genes. Following dissociation from the cytosolic protein Keap1, a scaffolding protein which binds Nrf2 and Cul3 ubiquitin ligase for proteasome degradation, Nrf2 rapidly accumulates in the nucleus and transactivates the antioxidant response element in the promoter region of many antioxidant genes. The critical role of Nrf2 has been demonstrated by various animal studies showing that mice with a targeted disruption of the nrf2 gene are prone to develop lesions in response to environmental toxicants/carcinogens, drugs, and inflammatory insults. In this review, we discuss the role of the Nrf2 system, with particular focus on Nrf2-controlled target genes and the potential pleiotropic effects of Nrf2 activation of indirect antioxidants.

Keywords: indirect antioxidants; oxidative stress; Nrf2; Keap1

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Slowing of axonal regeneration is correlated with increased axonal viscosity during aging

BMC Neuroscience 2010, 11:140doi:10.1186/1471-2202-11-140, Published: 25 October 2010

Phillip L Lamoureux, Matthew R O'Toole, Steven R Heidemann and Kyle E Miller

OPEN ACCESS

Conclusions
Taken together, our results suggest decreasing axonal stiffness may be part of an effective strategy to accelerate the regeneration of axons in the adult peripheral nervous system.

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Expression, Purification, and Characterization of an Iron Chaperon Protein CyaY from Acidithiobacillus ferrooxidans

Current Microbiology,DOI: 10.1007/s00284-010-9775-2

Chenbing Ai, Hongyu Mo, Qian Chen, Yuandong Liu, Lin Tang, Juan Du and Jia Zeng

Keywords: CyaY, bacterial homolog of frataxin, iron–sulfur clusters, Acidithiobacillus ferrooxidans, Escherichia coli, affinity chromatography, ferric iron, iron donor, scaffold protein IscU, IscS, l-cysteine.

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Genetic Engineering of Mesenchymal Stem Cells and Its Application in Human Disease Therapy

Conrad P. Hodgkinson, José A. Gomez, Maria Mirotsou, Victor J. Dzau. Human Gene Therapy. -Not available-, ahead of print. doi:10.1089/hum.2010.165.

Keywords: stem cells, tissue regeneration, bone marrow, therapeutic potential, cardiovascular injury, kidney failure, cancer, neurological and bone disorders. low survival, engraftment, inefficiencies in differentiating into fully functional tissues, genetic engineering, mesenchymal stem cells, genetic modifications.

Dynamics of Protein Damage in Yeast Frataxin Mutant Exposed to Oxidative Stress.

OMICS. 2010 Oct 20. [Epub ahead of print]
Kim JH, Sedlak M, Gao Q, Riley CP, Regnier FE, Adamec J.
Bindley Bioscience Center at Discovery Park, Purdue University , West Lafayette, Indiana.

Keywords: Oxidative stress, protein carbonylation, aging, neurodegenerative disorders, diabetes, cancer, biomarkers, energy metabolism, peroxiredoxin (TSA1), thioredoxin II (TRX2).

Frataxin is an important regulator of iron metabolism

MRC, National Institute for Medical Research, 20 October 2010

Brief summary of the article by Dr. Annalisa Pastore, explaining their research in words more simple and comprehensible to all

Frataxin depletion in yeast triggers upregulation of iron transport systems before affecting iron-sulfur enzyme activities.

J Biol Chem. 2010 Oct 18. [Epub ahead of print]
Moreno-Cermeno A, Obis E, Belli G, Cabiscol E, Ros J, Tamarit J.

University of Lleida, Spain.

Keywords: frataxin, a mitochondrial protein, iron homeostasis, yeast model, frataxin homolog YFH1, aconitase, secondary events, iron overloading, superoxide dismutase, protein carbonyl formation, manganese, metal ion transporter Smf2.

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Pharmacokinetic evaluation of idebenone.

Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1437-44.

Becker C, Bray-French K, Drewe J.
Basel Pharmacoepidemiology Unit, University Hospital Basel, Switzerland.

Conclusions: Idebenone shows dose-proportional pharmacokinetics in healthy subjects in daily doses up to 2250 mg, and was safe and well tolerated at doses up to 2250 mg/day, in clinical studies.

Pathogenesis of impaired glucose tolerance and diabetes in Friedreich's ataxia: contribution of insulin resistance and pancreatic beta cell dysfunction.

The free library,
Miriam Cnop, MD, PhD, Universite Libre de Bruxelles, Brussels, Belgium

Research summary

Keywords: pancreatic b cells, Friedreich's ataxia, insulin demand.

Structural bases for the interaction of frataxin with the central components of iron–sulphur cluster assembly

Nature Communications, Volume:1, Article number: 95, DOI: doi:10.1038/ncomms1097
Received 08 June 2010, Accepted 22 September 2010, Published 19 October 2010

National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
* Filippo Prischi,
* Clara Iannuzzi,
* Chiara Pastore,
* Salvatore Adinolfi,
* Stephen R. Martin &
* Annalisa Pastore
European Molecular Biology Laboratory, EMBL c/o DESY, Notkestrasse 85, Hamburg D-22603, Germany.
* Petr V. Konarev &
* Dmitri I. Svergun

OPEN ARTICLE

Mitochondrial ROS Generation and Its Regulation: Mechanisms Involved in H2O2 Signaling

Antioxidants & Redox Signaling. Online Ahead of Print: October 18, 2010, doi:10.1089/ars.2010.3363.
Michel Rigoulet, Edgar D. Yoboue, Anne Devin. Université Bordeaux 2, and Institute of Biochemistry and Genetics of the Cell (IBGC) du CNRS, Bordeaux, France.

Keyworsd: Mitochondria, reactive oxygen species, oxidative stress, respiratory chain, dehydrogenases, bc1 complex, complex I, signaling molecules.

Public summary of opinion on orphan designationN-(6-(2-aminophenylamino)-6-oxohexyl)-4-methylbenzamide for the treatment of Friedreich’s ataxia,

12 October 2010
EMA/COMP/455242/2010
Committee for Orphan Medicinal Products.

On 1 October 2010, orphan designation (EU/3/10/793) was granted by the European Commission to Repligen Europe Limited, Ireland, for N-(6-(2-aminophenylamino)-6-oxohexyl)-4-methylbenzamide for the treatment of Friedreich’s ataxia.

Induced pluripotency: history, mechanisms, and applications

Genes & Dev. 2010. 24: 2239-2263, doi: 10.1101/gad.1963910
Matthias Stadtfeld, Konrad Hochedlinger

(REVIEWS)

OPEN ACCESS

The generation of induced pluripotent stem cells (iPSCs) from somatic cells demonstrated that adult mammalian cells can be reprogrammed to a pluripotent state by the enforced expression of a few embryonic transcription factors.

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In vivo evidence for the iron binding activity of an iron-sulfur cluster assembly protein IscA in Escherichia co

Biochem. J. (2010) Immediate Publication, doi:10.1042/BJ20101507

Wu Wang, Hao Huang, Guoqiang Tan, Fan Si, Min Liu, Aaron P. Landry, Jianxin Lu and Huangen Ding
Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, U.S.A.

"IscU, a proposed iron-sulfur cluster assembly scaffold protein, and CyaY, a bacterial frataxin homolog that has been postulated as an iron donor for the iron-sulfur cluster assembly, fail to bind any iron in E. coli cells under the same experimental conditions"

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Epigenetic modifications and human disease

Nature Biotechnology, Volume:28, Pages:1057–1068,Year published:(2010)
DOI:10.1038/nbt.1685, Published online 13 October 2010

Anna Portela & Manel Esteller
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
Manel Esteller
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.

Epigenetic modifications in neurodegenerative and neurological diseases (Friedreich's ataxia) , Epigenetic modifications in neurodevelopmental disorder

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Epigenetic modifications as therapeutic targets

Nature Biotechnology, Volume: 28 ,Pages: 1069–1078,Year published:(2010)
DOI:10.1038/nbt.1678, Published online 13 October 2010

Theresa K Kelly, Daniel D De Carvalho & Peter A Jones Departments of Urology and Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

The paper focus on recent examples in which epigenetic modifications have been used to evaluate disease risk, progression and clinical response. It provide a broad overview of the accomplishments, remaining challenges and unrealized potential of epigenetic therapies in a range of diseases, with a particular emphasis on cancer.

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On the Trail of the Epigenetic Code: Test System on Drosophila Should Provide the Key to Histone Function

ScienceDaily (Oct. 12, 2010) — Test system on Drosophila should provide the key to histone function. The genetic inherited material DNA was long viewed as the sole bearer of hereditary information. The function of its packaging proteins, the histones, was believed to be exclusively structural. Additional genetic information can be stored, however, and passed on to subsequent generations through chemical changes in the DNA or histones. read more

Original paper: A genetic system to assess in vivo the functions of histones and histone modifications in higher eukaryotes

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Kinematic analysis of lingual movements during consonant productions in dysarthric speakers with Friedreich's ataxia: A case-by-case analysis.

Clin Linguist Phon. 2010 Oct 8. [Epub ahead of print]

Folker JE, Murdoch BE, Cahill LM, Delatycki MB, Corben LA, Vogel AP.

School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, QLD, Australia.

An in Vivo Method for Characterization of Protein Interactions within Sulfur Trafficking Systems of E. coli

J. Proteome Res., Just Accepted Manuscript, DOI: 10.1021/pr100920r
Publication Date (Web): October 11, 2010

Heather May Bolstad and Matthew James Wood

KEYWORDS: iron-sulfur clusters, in vivo method, mass spectrometry, iron-sulfur biogenesis, general tool for the determination of sulfur trafficking mechanisms.

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Dizziness in Orthopaedic Physical Therapy Practice: History and Physical Examination

The Journal of Manual & Manipulative Therapy
Vol. 13 No. 4 (2005), 222 - 251

Paul Vidal, PT, MHSc, DPT, OCS, MTC
Peter Huijbregts, PT, MSc, MHSc, DPT, OCS, MTC, FAAOMPT, FCAMT


Physical therapy (PT) differential diagnosis of patients complaining of dizziness centers on distinguishing those patients who might benefit from sole management by the physical therapist from those patients who require referral for medical-surgical differential diagnosis and (co) management.....

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Microchip Technology Rapidly Identifies Compounds for Regrowing Nerves in Live Animals

ScienceDaily (Oct. 11, 2010) — Scientists have long sought the ability to regenerate nerve cells, or neurons, which could offer a new way to treat spinal-cord damage as well as neurological diseases such as Alzheimer's or Parkinson's. Many chemicals can regenerate neurons grown in Petri dishes in the lab, but it's difficult and time-consuming to identify those chemicals that work in live animals, which is critical for developing drugs for humans. read more

Evaluation of neuropsychological functions in patients with Friedreich ataxia before and after cognitive therapy

Funct Neurol. 2010 Apr-Jun;25(2):81-5.
Ciancarelli I, Cofini V, Carolei A.

Keywords: Friedreich ataxia (FA, severe disability, cognitive functions, mood disorders, conflicting results, role of cognitive rehabilitation therapy, MMSE, Rey 15-item Memorization Test, Raven's Colored Progressive Matrices, the Phonemic Verbal Fluency Test, the Symbol Digit Modalities Test, Zung scale.

Remarkably Efficient New Method For Generating Human Stem Cells

Medical News Today, Article Date: 02 Oct 2010 - 0:00 PDT

The ability to efficiently generate patient-specific stem cells from differentiated cells and then reliably direct them to form specialized cells (like neurons or muscle) has tremendous therapeutic potential for replacing diseased or damaged tissues... read more


Technology Review, Friday, October 1, 2010

A New Way to Make Stem Cells

Using RNA instead of DNA could avoid the health risks--and the political pitfalls--of stem-cell treatments.

A Harvard researcher has developed a way to make pluripotent stem cells that solves several of the major impediments to using them to treat human diseases. read more...

Normal and Friedreich ataxia cells express different isoforms of frataxin with complementary roles in iron-sulfur cluster assembly.

J Biol Chem. 2010 Oct 2. [Epub ahead of print]

Gakh O, Bedekovics T, Duncan SF, Smith DY 4th, Berkholz DS, Isaya G.
Mayo Clinic, United States.

Keywords: frataxin (FXN), Fe-S cluster, FXN mRNA, FXN42-210, FXN81-210, levels of both isoforms are relevant, FXN81-210/FXN42-210 molar ratio, replacement therapies.

PGC-1 Coactivators in Cardiac Development and Disease

Circulation Research. 2010;107:825-838
doi: 10.1161/CIRCRESAHA.110.223818

Daniel P. Kelly, Guest Editor
Glenn C. Rowe, Aihua Jiang, Zolt Arany

From the Cardiovascular Institute at the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.

Key Words: PGC-1 • metabolism • heart failure • mitochondria

Progress and prospects: stem cells and neurological diseases

Gene Therapy , (30 September 2010) | doi:10.1038/gt.2010.130

S Gögel, M Gubernator and S L Minger

Review.

Keywords: central nervous system, degenerative neurological conditions, Parkinson's disease (PD), Alzheimer's disease, Huntington's disease (HD), cerebrovascular damage (for example, stroke), spinal cord injury, transplantation of stem cells, stem cell-derived progenitors, induced pluripotent stem cells.

Spinal convergence of motor and sensory pathways

Nature Neuroscience 13, 1160 (2010)
Published online: 27 September 2010 | doi:10.1038/nn1010-1160

Min Cho

KEYWORDS: motor execution, proprioceptive sensory feedback, motor command.

Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex

Biochemistry, Just Accepted Manuscript
Publication Date (Web): September 27, 2010

Chi-Lin Tsai and David P. Barondeau, Department of Chemistry, Texas A&M
University, College Station, TX 77842, USA.

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Scientists Discover Gene That Controls Stem Cells In Central Nervous System

Medical News Today, 27 Sep 2010

"With the knowledge that the gene Sox9 plays a central role in the development of our nervous system, we are one step closer to being able to control stem cells in the brain and regenerate different kinds of nerve cells." ....read more....

Restless Legs and Substantia Nigra Hypoechogenicity are Common Features in Friedreich's Ataxia.

Cerebellum. 2010 Sep 24.

Synofzik M, Godau J, Lindig T, Schöls L, Berg D.

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Tübingen, Germany.

KEYWORDS: Friedreich's ataxia (FA), restless legs syndrome (RLS), multisystemic network dysfunction, peripheral neuropathy, disturbances in subcellular brain iron homeostasis.

Combined Therapy with Idebenone and Deferiprone in Patients with Friedreich's Ataxia.

Cerebellum. 2010 Sep 24.

Velasco-Sánchez D, Aracil A, Montero R, Mas A, Jiménez L, O'Callaghan M, Tondo M, Capdevila A, Blanch J, Artuch R, Pineda M.

Cardiology Department, Sant Joan de Déu Hospital and the University of Barcelona, 2, Passeig Sant Joan de Déu, 08950 Esplugues, Barcelona, Spain

KEYWORDS: Iron chelators,Friedreich's ataxia, mitochondrial iron pools, neurological signs, cardiac function parameters, prospective open-label single-arm study, idebenone (20 mg/kg/day), deferiprone (20 mg/kg/day), International Cooperative Ataxia Rating Scale (ICARS) scores, echocardiographic measurements, MRI (magnetic resonance imaging) techniques, neutropenia, progressive reduction of plasma iron parameters.

Auszeichnung für neuen Therapieansatz bei Morbus Friedreich an MedUni Wien

Medizinische Universität Wien

(Wien, 21-09-2010) Barbara Scheiber-Mojdehkar und Brigitte Sturm vom Zentrum für Pathobiochemie und Genetik der MedUni Wien haben einen völlig neuen Therapieansatz zur Behandlung der neurodegenerativen Krankheit Friedreichs Ataxie entdeckt und dafür die Goldmedaille bei der Korea International Women`s Invention Exposition KIWIE 2010 erhalten. Heute fand die Überreichung durch Bundesministerin Dr.in Beatrix Karl statt.

"Award for new approach in the treatment of Friedreich's Disease by Medical University of Vienna"

Keyword: Iron chelators, neurodegenerative disease, Friedreich's ataxia, mitochondrial protein frataxin, erythropoietin.

The Impact of the Orphan Drug Act on the Development and Advancement of Neurological Products for Rare Diseases: A Descriptive Review

Clinical Pharmacology & Therapeutics (2010) 88 4, 449–453. doi:10.1038/clpt.2010.193

K A Burke1, S N Freeman1, M A Imoisili1 and T R Coté1
1Office of Orphan Products Development, US Food and Drug Administration, Silver Spring, Maryland, USA

Successful treatment of auditory perceptual disorder in individuals with Friedreich ataxia

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0F-511K412-6&_user=10&_coverDate=09%2F16%2F2010&_rdoc=1&_fmt=high&_orig=browse&_origin=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2cce40ce235d6a2b6e7401ca8adce6ff


Neuroscience, In Press, Uncorrected Proof, Available online 16 September 2010,doi:10.1016/j.neuroscience.2010.09.013

G. Rance a, L.A. Corben b, E. Du Bourg a, A. King c and M.B. Delatycki b

a Department of Otolaryngology, The University of Melbourne, Parkville, Victoria, Australia

b Bruce Lefroy Centre for Genetic Health Research, Parkville, Victoria, Australia

c Australian Hearing, Parkville, Victoria, Australia


Keywords: Friedreich's ataxia; auditory neuropathy; auditory processing; speech perception, personal-FM systems, communication difficulties.

Creating a global rare disease patient registry linked to a rare diseases biorepository database: Rare Disease-HUB (RD-HUB)☆

Contemporary Clinical Trials - September 2010 (Vol. 31, Issue 5, Pages 394-404, DOI: 10.1016/j.cct.2010.06.007)

Yaffa R. Rubinsteina, Stephen C. Grofta23, Ronald Bartekb, Kyle Brownc, Ronald A. Christensend, Elaine Colliere, Amy Farberf, Jennifer Farmerb, John H. Fergusona, Christopher B. Forrestgh, Nicole C. Lockharti, Kate R. McCurdyj, Helen Moorei, Geraldine B. Pollena, Rachel Richessonk, Vanessa Rangel Millerl, Sara Hullm, Jim Vaughti

a Office of Rare Diseases Research National Institutes of Health, Bethesda, MD, United States

b Friedreich's Ataxia Research Alliance (FARA), Springfield, VA, United States

c Innolyst, Inc, San Mateo, CA, United States

d REGISTRAT-MAPI, Scottsdale, AZ, United States

e National Center for Research Resources, National Institutes of Health, Bethesda, MD, United States

f LAM Treatment Alliance, Cambridge, MA, United States

g Children's Hospital of Philadelphia, Philadelphia, PA, United States

h Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States

i Office of Biorepositories and Biospecimen Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States

j Barth Syndrome Foundation, Inc, Larchmont, NY, United States

k Department of Pediatrics, Division of Bioinformatics and Biostatistics, University of South Florida College of Medicine, Tampa, FL, United States

l Department of Human Genetics, Emory University, Atlanta, GA, United States

m Office of the Clinical Director, National Human Genome Research Institute, Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, United States

☆ Authors listed 3rd to18th alphabetically contributed equally.

1 Director of Patient Resources for Clinical and Translational Research, Office of Rare Dieseases Reseach.

2 Director of the Office of Rare Diseases Research, National Institutes of Health, 6100 Executive Boulevard, Room 3A07, MSC-751, Bethesda, MD 20892, United States. Tel.: +1 301 435 6041.

3 Co-first author.

Keywords: FARA, Rare diseases, Patient registry, Disease registry, Patient advocacy, Biospecimen, Biospecimen repositories, Clinical data, Electronic health record

Long-Term IGF-I Exposure Decreases Autophagy and Cell Viability

PLoS One. 2010; 5(9): e12592.
Published online 2010 September 7. doi: 10.1371/journal.pone.0012592.

Alessandro Bitto,1 Chad Lerner,1 Claudio Torres,1 Michaela Roell,2 Marco Malaguti,2 Viviana Perez,3 Antonello Lorenzini,1,2 Silvana Hrelia,3 Yuji Ikeno,4 Michelle Elizabeth Matzko,5 Roger McCarter,4 and Christian Sell1*
1Department of Pathology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
2Department of Biochemistry, “G. Moruzzi” University of Bologna, Bologna, Italy
3Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
4Barshop Institute for Longevity and Aging Studies and Department of Pathology, University of Texas Health Science Center at San Antonio, Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio, Texas, United States of America
5Department of Biobehavioral Health, Penn State University, State College, Pennsylvania, United States of America
Matt Kaeberlein, Editor
University of Washington, United States of America


Abstrac

A reduction in IGF-I signaling has been found to increase lifespan in multiple organisms despite the fact that IGF-I is a trophic factor for many cell types and has been found to have protective effects against multiple forms of damage in acute settings. The increase in longevity seen in response to reduced IGF-I signaling suggests that there may be differences between the acute and chronic impact of IGF-I signaling. We have examined the possibility that long-term stimulation with IGF-I may have a negative impact at the cellular level using quiescent human fibroblasts. We find that fibroblast cells exposed to IGF-I for 14 days have reduced long-term viability as judged by colony forming assays, which is accompanied by an accumulation of senescent cells. In addition we observe an accumulation of cells with depolarized mitochondria and a reduction in autophagy in the long-term IGF-I treated cultures. An examination of mice with reduced IGF-I levels reveals evidence of enhanced autophagy and fibroblast cells derived from these mice have a larger mitochondrial mass relative to controls indicating that changes in mitochondrial turnover occurs in animals with reduced IGF-I. The results indicate that chronic IGF-I stimulation leads to mitochondrial dysfunction and reduced cell viability.

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Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron–sulfur cluster biogenesis

Hum. Mol. Genet. (2010) doi: 10.1093/hmg/ddq301

Helge Uhrigshardt 1,2,Anamika Singh 1,Gennadiy Kovtunovych 1,Manik Ghosh 1 and Tracey A. Rouault 1.

1 Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA and 2.JHU-Bayview Proteomics Center, Johns Hopkins University, School of Medicine, 5200 Eastern Avenue, Baltimore, MD 21224, USA

The Friedreich’s Ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals

Biochem. J. (2010) Immediate Publication, doi:10.1042/BJ20101116

René Thierbach, Gunnar Drewes, Markus Fußer, Anja Voigt, Doreen Kuhlow, Urte Blume, Tim J Schulz, Carina Reiche, Hansruedi Glatt, Bernd Epe, Pablo Steinberg and Michael Ristow

Department of Human Nutrition, University of Jena, Jena 07743, Germany. 

 

Keywords:  DNA repair mechanisms,  iron-sulphur-clusters (ISCs),  frataxin, Friedreich’s Ataxia,  cancer, 8-oxoguanine glycosylase.

 

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Molecular details of the yeast frataxin-Isu1 interaction during mitochondrial Fe-S cluster assembly

Biochemistry, Just Accepted Manuscript, DOI: 10.1021/bi1008613,Publication Date (Web): September 3, 2010

 

Jeremy D. Cook , Kalyan C. Kondapalli , Swati Rawat , William C. Childs , Yogapriya Murugesan , Andrew Dancis , and Timothy Louis Stemmler 

 

Keywords: Iron Chaperone, Frataxin, Yfh1, Isu1, Nfs1, NMR, ITC, Iron-Sulfur Cluster Assembly.

 

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Protective effects of transduced PEP-1-Frataxin protein on oxidative stress-induced neuronal cell death

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T06-50XV3JF-3&_user=10&_coverDate=09%2F03%2F2010&_rdoc=1&_fmt=high&_orig=browse&_origin=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2724eb2d4f21f0930a937b602939f104

Journal of the Neurological Sciences, In Press, Corrected Proof, Available online 3 September 2010,
Mi Jin Kim, Dae Won Kim, Ki-Yeon Yoo, Eun Jeong Sohn, Hoon Jae Jeong, Hye Won Kang, Min Jea Shin, Eun Hee Ahn, Jae Jin An, Soon Won Kwon, Young Nam Kim, Moo Ho Won, Sung-Woo Cho, Jinseu Park, Won Sik Eum and Soo Young Cho

Keywords:  Antioxidant; PEP-1-Frataxin; Protein transduction; Cell viability; Ischemia; ROS

New Research Demonstrates Safety Of Cord-blood-derived Stem Cell Treatments

Medical news Today, Article Date: 03 Sep 2010

In a new peer-reviewed article published by the Journal of Translational Medicine, scientists from Beike Biotechnology, China's leading stem cell research and regenerative medicine company, and Medistem, Inc., reported positive safety data in 114 patients who were treated by doctors at Nanshan Affiliated Hospital of Guangdong Medical College (Shenzhen Nanshan Hospital) in Shenzhen using Beike's proprietary cord blood stem cell transplantation protocol. ...read more...

Original source: Safety evaluation of allogeneic umbilical cord blood mononuclear cell therapy for degenerative conditions

Journal of Translational Medicine 2010, 8:75doi:10.1186/1479-5876-8-75

Wan-Zhang Yang1 email, Yun Zhang2 email, Fang Wu1 email, Wei-Ping Min3 email, Boris Minev4 email, Min Zhang1 email, Xiao-Ling Luo2 email, Famela Ramos5 email, Thomas E Ichim5 email, Neil H Riordan5* email and Xiang Hu2*


Background

The current paradigm for cord blood transplantation is that HLA matching and immune suppression are strictly required to prevent graft versus host disease (GVHD). Immunological arguments and historical examples have been made that the use of cord blood for non-hematopoietic activities such as growth factor production, stimulation of angiogenesis, and immune modulation may not require matching or immune suppression.

Methods

114 patients suffering from non-hematopoietic degenerative conditions were treated with non-matched, allogeneic cord blood. Doses of 1-3 × 107 cord blood mononuclear cells per treatment, with 4-5 treatments both intrathecal and intravenously were performed. Adverse events and hematological, immunological, and biochemical parameters were analyzed for safety evaluation.

Results

No serious adverse effects were reported. Hematological, immunological, and biochemical parameters did not deviate from normal ranges as a result of therapy.

Conclusion

The current hematology-based paradigm of need for matching and immune suppression needs to be revisited when cord blood is used for non-hematopoietic regenerative purposes in immune competent recipients.

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Protocol proposal for Friedreich ataxia molecular diagnosis using fluorescent and triplet repeat primed polymerase chain reaction

LINK: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B83WW-50X8GB2-1&_user=10&_coverDate=08%2F31%2F2010&_rdoc=1&_fmt=high&_orig=browse&_origin=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=8b4ac06505c1ed6fa9282efeaeeed2fd

Translational Research. Article in Press.
doi:10.1016/j.trsl.2010.08.001

Mar Xunclàa, b, Laia Rodríguez-Revengaa, c, Irene Madrigala, c, Dolores Jiméneza, Montserrat Milàa, c, d and Cèlia Badenasa, c, d,

a Biochemistry and Molecular Genetics Service. Hospital Clínic, b Fundació Clínic per a la Recerca Biomèdica, c CIBER de Enfermedades Raras, d Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

Researchers Develop Hybrid Protein Tools For Gene Cutting And Editing

MedicalNews Today, Article Date: 31 Aug 2010

An Iowa State University team of researchers has developed a type of hybrid proteins that can make double-strand DNA breaks at specific sites in living cells, possibly leading to better gene replacement and gene editing therapies. Read more

[Distribution of frataxin in eye retina of normal mice and of transgenic R7E mice with retinal degeneration]

Zh Evol Biokhim Fiziol. 2010 Jul-Aug;46(4):347-9.

[Article in Russian]

Development of a potential therapy for Friedreich ataxia based on transduction of the frataxin protein in the mitochondria

Canadian Association for Familial Ataxias - Claude St-Jean Foundation
August 25, 2010,

CAFA IS LAUNCHING A MAJOR RESEARCH PROJECT

This research project’s goal is to develop a therapy for Friedreich ataxia by targeting the actual cause of the illness, the reduction of frataxin. The project will therefore aim to administer the frataxin protein intravenously. However, as this protein does not spontaneously penetrate cells, it will be encapsulated with peptides (fragments of other proteins), in nanoparticles. Alternatively, the frataxin protein itself will be modified by adding peptides which will allow the proteins to penetrate not only the interior of cells, but also the interior of the mitochondria.

Symposium participants optimistic about finding first treatment for Friedreich's ataxia

USF Health News, August 30, 2010 @ 4:58 pm

"With all the significant scientific advancements presented, at the end of the symposium it was the people with Friedreich’s ataxia who gave the research meaning and value"

Proteomic Analysis of Protein-Protein Interactions within the CSD Fe-S Cluster Biogenesis System

J. Proteome Res., Just Accepted Manuscript, Publication Date (Web): August 24, 2010

Heather May Bolstad , Danielle J Botelho and Matthew James Wood

Keygen: Fe-S cluster biogenesis, cysteine desulfurase CsdA, sulfur acceptor protein CsdE, E1-like protein CsdL. Fe-S cluster assembly (ErpA, glutaredoxin-3, glutaredoxin-4), sulfur trafficking (CsdL, YchN) proteins, two-pathway model.

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Lipid Peroxides: More Sophisticated Than Their Reputation

ScienceDaily (Aug. 24, 2010) — Accumulation of lipid peroxides in the cell are associated with diseases and cellular stress. In the current issue of Proceedings of the National Academy of Sciences, researchers at Helmholtz Zentrum München and the Swedish medical university Karolinska Institutet show that lipid peroxides also play an important, yet-unrecognized role in the regulation of receptor tyrosine kinases.

Reference scientific paper:
12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.
M. Conrad, A. Sandin, H. Forster, A. Seiler, J. Frijhoff, M. Dagnell, G. W. Bornkamm, O. Radmark, R. Hooft van Huijsduijnen, P. Aspenstrom, F. Bohmer, A. Ostman. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1007909107

The Monash University are seeking healthy participants for the control group, Understanding Motor Deficits in Friedreich's Ataxia

The aim of this study is to investigate the extent of motor overflow in people with Friedreich's ataxia. Motor overflow refers to involuntary movement which occurs on the opposite side of the body when voluntary movement takes place on one side.

Defects in Mitochondrial Axonal Transport and Membrane Potential without Increased Reactive Oxygen Species Production in a Drosophila Model of Friedreich Ataxia

The Journal of Neuroscience, August 25, 2010, 30(34):11369-11378; doi:10.1523/JNEUROSCI.0529-10.2010

Yujiro Shidara {dagger} and Peter J. Hollenbeck
Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907

KEYWORDS: Friedreich ataxia, frataxin deficiency, oxidative stress, cellular neuropathology, mitochondrial axonal transport, membrane potential (MMP), reactive oxygen species (ROS), neuromuscular junctions (NMJs), antimycin A.

Long-term effects of coordinative training in degenerative cerebellar disease†

Movement Disorders, Article first published online: 24 AUG 2010, DOI: 10.1002/mds.23222

Winfried Ilg PhD1, Doris Brötz PT2, 3. Susanne Burkard PT3, Martin A. Giese PhD1, Ludger Schöls MD4,*, Matthis Synofzik MD4.

Prospects for the Use of Artificial Chromosomes and Minichromosome-Like Episomes in Gene Therapy

Journal of Biomedicine and Biotechnology, Volume 2010 (2010), Article ID 642804, 16 pages, doi:10.1155/2010/642804

Sara Pérez-Luz1,2,3 and Javier Díaz-Nido1,2,3

1Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), C/Nicolás Cabrera 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain
3U-748, Area de Neurogenética, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain

OPEN ACCESS

Abstract

Artificial chromosomes and minichromosome-like episomes are large DNA molecules capable of containing whole genomic loci, and be maintained as nonintegrating, replicating molecules in proliferating human somatic cells. Authentic human artificial chromosomes are very difficult to engineer because of the difficulties associated with centromere structure, so they are not widely used for gene-therapy applications. However, OriP/EBNA1-based episomes, which they lack true centromeres, can be maintained stably in dividing cells as they bind to mitotic chromosomes and segregate into daughter cells. These episomes are more easily engineered than true human artificial chromosomes and can carry entire genes along with all their regulatory sequences. Thus, these constructs may facilitate the long-term persistence and physiological regulation of the expression of therapeutic genes, which is crucial for some gene therapy applications. In particular, they are promising vectors for gene therapy in inherited diseases that are caused by recessive mutations, for example haemophilia A and Friedreich's ataxia. Interestingly, the episome carrying the frataxin gene (deficient in Friedreich's ataxia) has been demonstrated to rescue the susceptibility to oxidative stress which is typical of fibroblasts from Friedreich's ataxia patients. This provides evidence of their potential to treat genetic diseases linked to recessive mutations through gene therapy.

Section: "4.4. Gene Therapy for Friedreich’s Ataxia"

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Mitochondrial protein import: from proteomics to functional mechanisms

Nature Reviews Molecular Cell Biology 11, 655–667 (1 September 2010) | doi:10.1038/nrm2959

Oliver Schmidt , Nikolaus Pfanner & Chris Meisinger

Keywords: Mitochondria, proteins, cytosol, import pathways, protein translocases.

Cytosolic Iron-Sulfur Cluster Assembly (CIA) System: Factors, Mechanism, and Relevance to Cellular Iron Regulation

J. Biol. Chem. 2010 285: 26745-26751. doi:10.1074/jbc.R110.122218

Anil K Sharma, Leif J Pallesen, Robert J Spang and William E Walden*

University of Illinois at Chicago, United States

KEYWORDS: Iron sulfur (FeS) cluster biogenesis, cellular iron homeostasis.

Expression of Human Frataxin Is Regulated by Transcription Factors SRF and TFAP2

Li K, Singh A, Crooks DR, Dai X, Cong Z, et al. 2010 . PLoS ONE 5(8): e12286. doi:10.1371/journal.pone.0012286

OPEN ACCESS

Abstract
Background

Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression.
Methodology/Principal Findings

We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2.
Conclusions/Significance

We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia.

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H MR Spectroscopy in Friedreich's Ataxia and Ataxia with Oculomotor Apraxia Type 2.

Brain Res. 2010 Aug 13. [Epub ahead of print]

Iltis I, Hutter D, Bushara KO, Clark HB, Gross M, Eberly LE, Gomez CM, Oz G.
Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, U.S.A.

Keywords: Friedreich's ataxia (FRDA, ataxia with oculomotor apraxia type 2 (AOA2), brain metabolism, biomarker of the disease progression, Friedreich's Ataxia Rating Scale (FARS), monitor disease progression.

First half report 2010 - Lundbeck

Lu AA24493 is in clinical phase II in the treatment of Friedreich's ataxia and
in clinical phase I in the treatment of acute ischaemic stroke. Ongoing studies
in both programmes are expected to be concluded in the second half of 2010.

Santhera Obtains European Patent for Use of Catena®/Sovrima®

Liestal, Switzerland, August 13, 2010 - Santhera Pharmaceuticals (SIX: SANN)
announced today that the European Patent Office granted patent protection for
the use of idebenone (brand name Catena®/Sovrima®) in the treatment of Duchenne
Muscular Dystrophy and other muscular dystrophies.

Friedreich’s Ataxia Induced Pluripotent Stem Cells Recapitulate GAA•TTC Triplet-Repeat Instability

NCBI, Public on Jul 02, 2010

Experiment type: Expression profiling by array

Keywords: Friedreich’s ataxia (FRDA), GAA•TTC trinucleotide repeats, FXN gene, induced pluripotent stem cells (iPSCs), fibroblasts, retroviral transduction, Msh2, repeat instability.

A Phase 3, Double-blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia

Arch Neurol. 2010;67(8):941-947. doi:10.1001/archneurol.2010.168

David R. Lynch, MD, PhD; Susan L. Perlman, MD; Thomas Meier, PhD  

 

Automated quantitative gait analysis in animal models of movement disorders

BMC Neuroscience 2010, 11:92doi:10.1186/1471-2202-11-92

Caroline Vandeputte, Jean-Marc Taymans, Cindy Casteels, Frea Coun, Yicheng Ni, Koen Van Laere and Veerle Baekelandt.

OPEN ACCESS

Conclusion

The automated quantitative gait analysis test may be a useful tool to study both motor impairment and recovery associated with various neurological motor disorders.

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Erythropoiesis and iron sulfur cluster biogenesis

Advances in Hematology, Received 1 March 2010; Revised 4 June 2010; Accepted 2 August 2010

Hong Ye and Tracey A. Rouault

OPEN ACCES

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Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.

Neurobiol Aging. 2010 Jul 29.

Wu Z, Du Y, Xue H, Wu Y, Zhou B.
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.

I would like to emphasize: .../... "suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity".../...

A rapid, noninvasive immunoassay for frataxin: Utility in assessment of Friedreich ataxia.

Mol Genet Metab. 2010 Jul 8. [Epub ahead of print]

Deutsch EC, Santani AB, Perlman SL, Farmer JM, Stolle CA, Marusich MF, Lynch DR.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Keywords: Friedreich ataxia (FRDA), frataxin, Western blot analysis, fibroblasts, lymphocytes, , muscle biopsies, lateral flow immunoassay, buccal cells.

Current and emerging treatment options in the management of Friedreich ataxia

Neuropsychiatric Disease and Treatment, Published Date July 2010 , Volume 2010:6 Pages 491 - 499

Michelangelo Mancuso, Daniele Orsucci, Anna Choub, Gabriele Siciliano
Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy

Keywords: Friedreich ataxia (FRDA), Oxidative damage, mitochondria, antioxidant protection, idebenone, cardiac hypertrophy, frataxin gene transcription, iron-chelating therapies, erythropoietin, histone deacetylase inhibitors, gene-based strategies.

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EMBL scientists identify proteins that ensure iron balance

EurekAlert, Public release date: 4-Aug-2010

MEASURING LEVELS OF FRATAXIN

Patent about methods and materials involved in measuring levels of a frataxin polypeptide present in a differents  biological samples.

MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH, OGLESBEE, Devin, MATERN, Dietrich, ISAYA, Grazia.

Adaptive robot training for the treatment of incoordination in Multiple Sclerosis

Journal of NeuroEngineering and Rehabilitation 2010, 7:37doi:10.1186/1743-0003-7-37

Elena Vergaro, Valentina Squeri, Giampaolo Brichetto, Maura Casadio, Pietro Morasso, Claudio Solaro and Vittorio Sanguineti.

OPEN ACCES

Abstract

Background
Cerebellar symptoms are extremely disabling and are common in Multiple Sclerosis (MS) patients. In this feasibility study, we developed and tested a robot therapy protocol, aimed at the rehabilitation of incoordination in MS subjects.

Methods
Eight subjects with clinically defined MS performed planar reaching movements while grasping the handle of a robotic manipulandum, which generated forces that either reduced (error-reducing, ER) or enhanced (error-enhancing, EE) the curvature of their movements, assessed at the beginning of each session. The protocol was designed to adapt to the individual subjects' impairments, as well as to improvements between sessions (if any). Each subject went through a total of eight training sessions. To compare the effect of the two variants of the training protocol (ER and EE), we used a cross-over design consisting into two blocks of sessions (four ER and four EE; 2 sessions/week), separated by a 2-week wash-out period. The order of application of ER and EE exercises was randomized across subjects. The primary outcome measure was the modification of the Nine Hole Peg Test (NHPT) score. Other clinical scales and movement kinematics were taken as secondary outcomes.

Results
Most subjects revealed a preserved ability to adapt to the robot-generated forces. No significant differences were observed in EE and ER training. However over sessions, subjects exhibited an average 24 % decrease in their NHPT score. The other clinical scales showed small improvements for at least some of the subjects. After training, movements became smoother, and their curvature decreased significantly over sessions.

Conclusions
The results point to an improved coordination over sessions, and suggest a potential benefit of a short-term, customized, and adaptive robot therapy for MS subjects.

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Development and pilot testing of HEXORR: Hand EXOskeleton Rehabilitation Robot

Journal of NeuroEngineering and Rehabilitation 2010, 7:36doi:10.1186/1743-0003-7-36

Christopher N Schabowsky, Sasha B Godfrey, Rahsaan J Holley and Peter S Lum.

OPEN ACCES

Abstract

Background
Following acute therapeutic interventions, the majority of stroke survivors are left with a poorly functioning hemiparetic hand. Rehabilitation robotics has shown promise in providing patients with intensive therapy leading to functional gains. Because of the hand's crucial role in performing activities of daily living, attention to hand therapy has recently increased.

Methods
This paper introduces a newly developed Hand Exoskeleton Rehabilitation Robot (HEXORR). This device has been designed to provide full range of motion (ROM) for all of the hand's digits. The thumb actuator allows for variable thumb plane of motion to incorporate different degrees of extension/flexion and abduction/adduction. Compensation algorithms have been developed to improve the exoskeleton's backdrivability by counteracting gravity, stiction and kinetic friction. We have also designed a force assistance mode that provides extension assistance based on each individual's needs. A pilot study was conducted on 9 unimpaired and 5 chronic stroke subjects to investigate the device's ability to allow physiologically accurate hand movements throughout the full ROM. The study also tested the efficacy of the force assistance mode with the goal of increasing stroke subjects' active ROM while still requiring active extension torque on the part of the subject.

Results
For 12 of the hand digits'15 joints in neurologically normal subjects, there were no significant ROM differences (P > 0.05) between active movements performed inside and outside of HEXORR. Interjoint coordination was examined in the 1st and 3rd digits, and no differences were found between inside and outside of the device (P > 0.05). Stroke subjects were capable of performing free hand movements inside of the exoskeleton and the force assistance mode was successful in increasing active ROM by 43 +/- 5% (P < 0.001) and 24 +/- 6% (P = 0.041) for the fingers and thumb, respectively. Conclusions Our pilot study shows that this device is capable of moving the hand's digits through nearly the entire ROM with physiologically accurate trajectories. Stroke subjects received the device intervention well and device impedance was minimized so that subjects could freely extend and flex their digits inside of HEXORR. Our active force-assisted condition was successful in increasing the subjects' ROM while promoting active participation.
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Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor

Brain 2010 133(8):2281-2294; doi:10.1093/brain/awq101

Stanislava Pankratova1, Darya Kiryushko1, Katrin Sonn2, Vladislav Soroka1, Lene B. Køhler1, Mette Rathje1, Bing Gu1, Kamil Gotfryd1, Ole Clausen1, Alexander Zharkovsky2, Elisabeth Bock1 and Vladimir Berezin1

1 Protein Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark 2 Department of Pharmacology, Centre of Excellence for Translational Medicine, University of Tartu, 51014 Tartu, Estonia

Keywords: Erythropoietin, central nervous system, neuroprotective agent, non-haematopoietic erythropoietin, Epotris, neurite outgrowth, blood–brain barrier, neurodegeneration, neurological disorders.

First causal treatment option for Friedreich's Ataxia via Erythropoietin (EPO)

Technology collaboration OFFER
Abstract
An Austrian university offers the first treatment option for Friedreich´s Ataxia (FRDA), an inherited neurodegenerative disease. It causally targets FRDA
using Erythropoietin (EPO) to increase the level of Frataxin, decreased levels of which are reportedly responsible for the development of FRDA. So far
no other effective treatment is available which is at an advanced development stage. Industrial partners for further developing & commercialising
EPO for the treatment of FRDA are sought.

Date de creation: 23 July 2010

Insulin signaling meets mitochondria in metabolism.

Trends Endocrinol Metab (2010), Published by Elsevier Ltd. DOI: 10.1016/j.tem.2010.06.005

Zhiyong Cheng, Yolanda Tseng and Morris F White
Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston MA, USA.

"chronic exposure to high ROS levels could alter mitochondrial function and thereby cause insulin resistance"

Klinik und Genetik der rezessiven Ataxien -[Clinical details and genetics of recessive ataxias.]

Nervenarzt. 2010 Jul 18. DOI: 10.1007/s00115-010-3079-4

Kühlke C, Kreuz F, Bürk K.

Institut für Humangenetik, Universität zu Lübeck.
[Article in German]

Iron-Sulfur (Fe-S) Cluster Assembly THE SufBCD COMPLEX IS A NEW TYPE OF Fe-S SCAFFOLD WITH A FLAVIN REDOX COFACTOR*

J. Biol. Chem. 2010 285: 23331-23341. First Published on May 11, 2010, doi:10.1074/jbc.M110.127449

Silke Wollers, Gunhild Layer, Ricardo Garcia-Serres, Luca Signor, Martin Clemancey, * Jean-Marc Latour, Marc Fontecave, and Sandrine Ollagnier de Choudens

ArmaGen® Re-engineers Erythropoietin For Brain Penetration

Medical News Today, Article Date: 17 Jul 2010

"EPO drug development for the brain is limited, because EPO does not cross the blood-brain barrier (BBB)"

"EPO-driven neuroprotection in human brain disorders is now possible with systemic administration of the HIRMAb-EPO fusion protein at doses that have minimal effects on erythropoiesis."

ArmaGen® Web

Oxidative stress, thiol redox signaling methods in epigenetics.

Methods Enzymol. 2010; 474: 213-44, doi:10.1016/S0076-6879(10)74013-1

Sundar IK, Caito S, Yao H, Rahman I

Keywords: Epigenetics, gene expression, posttranslational modifications, histones, histone acetylation, deacetylation, methylation, histone acetyltransferases (HATs), histone deacetylases (HDACs), reative oxygen species (ROS), signaling pathways, SIRT1.

Heterochromatin dysregulation in human diseases

J Appl Physiol 109: 232-242, 2010.
doi:10.1152/japplphysiol.00053.2010 

Matthias Hahn,^* Silvia Dambacher,^* and Gunnar Schotta
Munich Center for Integrated Protein Science (CiPS^M) and Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany 

Keywords: epigenetics, heterochromatin, epigenetic therapy, FSHD, Friedreich's ataxia (FRDA), cancer

The Intermembrane Space of Mitochondria

Antioxidants & Redox Signaling.  doi:10.1089/ars.2009.3063.

Johannes M. Herrmann and Jan Riemer

Department of Cell Biology, University of Kaiserslautern, Kaiserslautern, Germany.

Review: Friedreich Ataxia and Erythropoietin

The Open Drug Discovery Journal, Volume 2, ISSN: 1877-3818
Review: Friedreich Ataxia and Erythropoietin, pp.18-24 (7)
Authors: Sylvia Boesch, Brigitte Sturm, Wolfgang Nachbauer, Sascha Hering, Hannes Steinkellner, Rainer Schneider, Werner Poewe, Barbara Scheiber-Mojdehkar
doi: 10.2174/1877381801002020018
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Iron-Overload Cardiomyopathy: Pathophysiology, Diagnosis, and Treatment

Journal of Cardiac Failure, Article in Press, Corrected Proof. Available online 3 July 2010.

Colm J. Murphy MD, FRCPC and Gavin Y. Oudit MD, PhD, FRCPC
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada

Keywords: Cardiomyopathy; hemochromatosis; oxidative stress; anemia; cardiac MRI; echocardiography; primary (hereditary) hemochromatosis; secondary iron overload (hemosiderosis); iron toxicosis (iron poisoning); myocardial ischemia-reperfusion injury; cardiomyopathy associated with Friedreich ataxia; vascular dysfunction.

The Role of PGC-1alpha in the Pathogenesis of Neurodegenerative Disorders

Curr Drug Targets. 2010 Jul 1
Róna-Vörös K, Weydt P.
Department of Neurology, Ulm University, Ulm, Germany

Keywords: Mitochondrial dysfunction, neurodegeneration, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), transcriptional co-activator PGC-1alpha.

Assessment of impairment or monitoring change in Friedreich ataxia

Movement Disorders, 10.1002/mds.23103
Letter to the Editor

Adam P. Vogel, MSc 1 2 *, Angela T. Morgan, PhD 3 4
1Centre for Neuroscience, University of Melbourne, Australia
2Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia
3Department of Paediatrics, University of Melbourne, Australia
4Healthy Development Theme, Murdoch Childrens Research Institute, Melbourne, Australia

"No abstract"

PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload

Antioxidants & Redox Signaling. Ahead of print. doi:10.1089/ars.2009.2940.
Zhongbing Lu, Xin Xu, Xinli Hu, John Fassett, Guangshuo Zhu, Yi Tao, Jingxin Li, Yimin Huang, Ping Zhang, Baolu Zhao, Yingjie Chen.

Keywords: Mitochondria, reactive oxygen species (ROS, heart, Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α), SOD2, and thioredoxin (Trx2), 3’-nitrotyrosine, 4-hydroxynonenal, TAC-induced myocardial oxidative stress, hypertrophy,dysfunction.

Exercise Capacity and Idebenone Intervention in Children and Adolescents With Friedreich Ataxia

Archives of Physical Medicine and Rehabilitation, Vol=91, Issue 7, Pages 1044-1050 (July 2010)
( Presented in part to the American College of Sports Medicine, Seattle, WA, May 28, 2009.)

Drinkard BE, Keyser RE, Paul SM, Arena R, Plehn JF, Yanovski JA, Di Prospero NA. 

Keywords: Friedreich's Ataxia (FA), idebenone, randomized double-blind, placebo-controlled, oxidative stress, peak oxygen consumption per unit time (peak VO2), peak work rate (WR), Echocardiography, neurologic assessments, exercise.

Innovative gait robot for the repetitive practice of floor walking and stair climbing up and down in stroke patients

Journal of NeuroEngineering and Rehabilitation 2010, doi:10.1186/1743-0003-7-30

Stefan Hesse, Andreas Waldner; and Christopher Tomelleri

Published:28;June;2010

OPEN ACCES

Background

Stair climbing up and down is an essential part of everyday's mobility. To enable wheelchair-dependent patients the repetitive practice of this task, a novel gait robot, G-EO-Systems (EO, Lat: I walk), based on the end-effector principle, has been designed. The trajectories of the foot plates are freely programmable enabling not only the practice of simulated floor walking but also stair climbing up and down. The article intended to compare lower limb muscle activation patterns of hemiparetic subjects during real floor walking and stairs climbing up, and during the corresponding simulated conditions on the machine, and secondly to demonstrate gait improvement on single case after training on the machine.

Methods

The muscle activation pattern of seven lower limb muscles of six hemiparetic patients during free and simulated walking on the floor and stair climbing was measured via dynamic electromyography. A non-ambulatory, sub-acute stroke patient additionally trained on the G-EO-Systems every workday for five weeks.

Results

The muscle activation patterns were comparable during the real and simulated conditions, both on the floor and during stair climbing up. Minor differences, concerning the real and simulated floor walking conditions, were a delayed (prolonged) onset (duration) of the thigh muscle activation on the machine across all subjects. Concerning stair climbing conditions, the shank muscle activation was more phasic and timely correct in selected patients on the device. The severely affected subject regained walking and stair climbing ability.

Conclusions

The G-EO-Systems is an interesting new option in gait rehabilitation after stroke. The lower limb muscle activation patterns were comparable, a training thus feasible, and the positive case report warrants further clinical studies.

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Gene Therapy a Step Closer to Mass Production

ScienceDaily (June 24, 2010) — EUREKA project E! 3371 Gene Transfer Agents has made great advances in the development of novel non-viral carriers able to introduce genetic material into the target cells. These new agents, derivatives of cationic amphiphilic 1,4-dihydropyridine (1,4-DHP), avoid the problems of the recipient's immune system reacting against a viral carrier.

Transposon Tn7 Preferentially Inserts into GAA•TTC Triplet Repeats under Conditions Conducive to Y•R•Y Triplex Formation

Mancuso M, Sammarco MC, Grabczyk E, 2010 Transposon Tn7 Preferentially Inserts into GAA•TTC Triplet Repeats under Conditions Conducive to Y•R•Y Triplex Formation. PLoS ONE 5(6): e11121. doi:10.1371/journal.pone.0011121

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Abstract

BACKGROUND: Expansion of an unstable GAA*TTC repeat in the first intron of the FXN gene causes Friedreich ataxia by reducing frataxin expression. Structure formation by the repeat has been implicated in both frataxin repression and GAA*TTC instability. The GAA*TTC sequence is capable of adopting multiple non-B DNA structures including Y*R*Y and R*R*Y triplexes. Lower pH promotes the formation of Y*R*Y triplexes by GAA*TTC. Here we used the bacterial transposon Tn7 as an in vitro tool to probe whether GAA*TTC repeats can attract a well-characterized recombinase. METHODOLOGY/PRINCIPAL FINDINGS: Tn7 showed a pH-dependent preference for insertion into uninterrupted regions of a Friedreich ataxia patient-derived repeat, inserting 48, 39 and 14 percent of the time at pH 7, pH 8 and pH 9, respectively. Moreover, Tn7 also showed orientation and region specific insertion within the repeat at pH 7 and pH 8, but not at pH 9. In contrast, transposon Tn5 showed no strong preference for or against the repeat during in vitro transposition at any pH tested. Y*R*Y triplex formation was reduced in predictable ways by transposon interruption of the GAA*TTC repeat. However, transposon interruptions in the GAA*TTC repeats did not increase the in vitro transcription efficiency of the templates. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that transposon Tn7 will recognize structures that form spontaneously in GAA*TTC repeats and insert in a specific orientation within the repeat. The conditions used for in vitro transposition span the physiologically relevant range suggesting that long GAA*TTC repeats can form triplex structures in vivo, attracting enzymes involved in DNA repair, recombination and chromatin modification.

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Researchers create new 'smart' nanocapsule delivery system for use in protein therapy

UCLA Newsroom, Wileen Wong Kromhout December 17, 2009


Protein therapy — the delivery of healthy proteins directly into human cells to replace malfunctioning proteins — is considered one of the most direct and safe approaches for treating diseases. But its effectiveness has been limited by low delivery efficiency and the poor stability of proteins, which are frequently broken down and digested by cells' protease enzymes before they reach their intended target.     read more

More Discovered About The Composition Of Human Spinal Fluid

Medicalnewstoday, Article Date: 12 Jun 2010

A team of scientsts has sharply expanded scientific knowledge of the composition of human spinal fluid. The researchers have identified 2,630 proteins that reside in fluid that is considered "normal," a number nearly three times as great as the total number of proteins previously identified. Another striking finding was that more than half (56%) of the proteins were relatively unique to the spinal fluid and not found in blood.    read more

Longitudinal tracking of gait and balance impairments in cerebellar disease

Movement Disorders, Published Online: 11 Jun 2010, DOI 10.1002/mds.23169

Sussanne M. Morton, PhD, PT 1, Ya-Weng Tseng, PhD, PT 2, Kathleen M. Zackowski, PhD, OTR 3 4 5, Jaclyn R. Daline, PT, DPT 6, Amy J. Bastian, PhD, PT 3 4 5 *
1Graduate Program in Physical Therapy and Rehabilitation Science, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
2Department of Physical Therapy, Temple University, Philadelphia, Pennsylvania, USA
3Kennedy Krieger Institute, Baltimore, Maryland, USA
4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
5Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
6Program in Physical Therapy, Washington University School of Medicine, St. Louis, Missouri, USA

Keywords: ICARS,cerebellum, walking, ataxia, clinical assessment, sensitivity