NMR assignments of a stable processing intermediate of human frataxin

Biomolecular NMR Assignments, ISSN1874-2718 (Print) 1874-270X (Online), DOI10.1007/s12104-010-9209-x

Kalyan C. Kondapalli¹, Krisztina Z. Bencze¹, Eric Dizin², James A. Cowan² and Timothy L. Stemmler¹

(1)	Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA

(2)	Evans Laboratory of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA

Received: 25 September 2009  Accepted: 10 January 2010  Published online: 28 January 2010 

Keywords:  Friedreich’s ataxia - Iron chaperone - Frataxin - Iron-sulfur cluster biosynthesis - ISU 

Cardiac manifestations of neuromuscular disorders in children

Daphne T. Hsu
Children's Hospital at Montefiore and the Albert Einstein College of Medicine, 3415 Bainbridge Avenue, Bronx, New York 10467

Keywords: Cardiac abnormalities, neuromuscular disorders, cytoskeleton, nuclear membrane, mitochondrial function, muscular dystrophies- Duchenne, Becker, limb-girdle and Emery Dreifuss, Friedreich Ataxia, myotonic dystrophy, dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, atrial fibrillation and ventricular arrhythmias.

Uncommon Features in Cuban Families Affected with Friedreich Ataxia

Neuroscience Letters
Article in Press, Accepted Manuscript
 
Tania Cruz Mariñoa, , , Yanetza González Zaldivarb, Jose Miguel Laffita Mesab, Luis Almaguer Mederosb, Raul Aguilera Rodríguezb, Dennis Almaguer Gotayb, Roberto Rodríguez Labradab, Nalia Canales Ochoab, Patrick MacLeodc and Luis Velázquez Pérezb, ,


a Center of Medical Genetics, Holguín, Cuba
b Center for Research and Rehabilitation of Hereditary Ataxias “Carlos Juan Finlay” (CIRAH), Holguín, Cuba
c Division of Medical Genetics, Department of Pathology, Laboratory Medicine and Medical Gentics, Victoria General Hospital, Canada

Received 15 September 2009; revised 23 December 2009; accepted 21 January 2010. Available online 28 January 2010.

A high throughput electrochemiluminescence assay for the quantification of frataxin protein levels.

Anal Chim Acta. 2010 Feb 5;659(1-2):129-132. Epub 2009 Nov 27.

Steinkellner H, Scheiber-Mojdehkar B, Goldenberg H, Sturm B.
Medical University of Vienna, Department of Medical Chemistry, Waehringerstr. 10, 1090 Vienna, Austria.

Keywords: Friedreich's ataxia (FRDA), GAA-trinucleotide expansion, frataxin, measuring frataxin protein levels, electrochemiluminescence assay (ECLIA), human and mouse samples, highly quantitative, accurate, reproducible, low intra- and inter-assay error, new tool.

Automatic method of pause measurement for normal and dysarthric speech.

Clin Linguist Phon. 2010 Feb;24(2):141-54.

Rosen K, Murdoch B, Folker J, Vogel A, Cahill L, Delatycki M, Corben L.

The University of Queensland, Brisbane, Australia.

Keywords:  conversational speech,  Friedreich's Ataxia (FRDA).

Flavin Adenine Dinucleotide Rescues the Phenotype of Frataxin Deficiency

Gonzalez-Cabo P, Ros S, Palau F (2010) Flavin Adenine Dinucleotide Rescues the Phenotype of Frataxin Deficiency. PLoS ONE 5(1): e8872. doi:10.1371/journal.pone.0008872

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Pilar Gonzalez-Cabo^1,2#, Sheila Ros^1,2#¤, Francesc Palau^1,2*

1 Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain, 2 CIBER de Enfermedades Raras (CIBERER), Valencia, Spain

Abstract

Background

Friedreich ataxia is a neurodegenerative disease caused by the lack of frataxin, a mitochondrial protein. We previously demonstrated that frataxin interacts with complex II subunits of the electronic transport chain (ETC) and putative electronic transfer flavoproteins, suggesting that frataxin could participate in the oxidative phosphorylation.

Methods and Findings

Here we have investigated the effect of riboflavin and its cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in Saccharomyces cerevisiae and Caenorhabditis elegans models of frataxin deficiency. We used a S. cerevisiae strain deleted for the yfh1 gene obtained by homologous recombination and we assessed growth in fermentable and non-fermentable cultures supplemented with either riboflavin or its derivates. Experiments with C. elegans were performed in transient knock-down worms (frh-1[RNAi]) generated by microinjection of dsRNA frh-1 into the gonads of young worms. We observed that FAD rescues the phenotype of both defective organisms. We show that cell growth and enzymatic activities of the ETC complexes and ATP production of yfh1Δ cells were improved by FAD supplementation. Moreover, FAD also improved lifespan and other physiological parameters in the C. elegans knock-down model for frataxin.

Conclusions/Significance

We propose that rescue of frataxin deficiency by FAD supplementation could be explained by an improvement in mitochondrial respiration. We suggest that riboflavin may be useful in the treatment of Friedreich ataxia.

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Activities of daily living scale--the tool for clinical state monitoring of spinocerebellar ataxia and Friedreich ataxia patients.

Renaissance Medical Publishing

Two New Pimelic Diphenylamide HDAC Inhibitors Induce Sustained Frataxin Upregulation in Cells from Friedreich's Ataxia Patients and in a Mouse Model

Myriam Rai1, Elisabetta Soragni2, C. James Chou2¤, Glenn Barnes3, Steve Jones3, James R. Rusche3, Joel M. Gottesfeld2, Massimo Pandolfo1*


1 Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Brussels, Belgium, 2 Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America, 3 Repligen Corporation, Waltham, Massachusetts, United States of America

OPEN ACCES

Abstract
Background

Friedreich's ataxia (FRDA), the most common recessive ataxia in Caucasians, is due to severely reduced levels of frataxin, a highly conserved protein, that result from a large GAA triplet repeat expansion within the first intron of the frataxin gene (FXN). Typical marks of heterochromatin are found near the expanded GAA repeat in FRDA patient cells and mouse models. Histone deacetylase inhibitors (HDACIs) with a pimelic diphenylamide structure and HDAC3 specificity can decondense the chromatin structure at the FXN gene and restore frataxin levels in cells from FRDA patients and in a GAA repeat based FRDA mouse model, KIKI, providing an appealing approach for FRDA therapeutics.

Methodology/Principal Findings

In an effort to further improve the pharmacological profile of pimelic diphenylamide HDACIs as potential therapeutics for FRDA, we synthesized additional compounds with this basic structure and screened them for HDAC3 specificity. We characterized two of these compounds, 136 and 109, in FRDA patients' peripheral blood lymphocytes and in the KIKI mouse model. We tested their ability to upregulate frataxin at a range of concentrations in order to determine a minimal effective dose. We then determined in both systems the duration of effect of these drugs on frataxin mRNA and protein, and on total and local histone acetylation. The effects of these compounds exceeded the time of direct exposure in both systems.

Conclusions/Significance

Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACIs for FRDA and provide information for the design of future human trials of these drugs, suggesting an intermittent administration of the drug.

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Aaron G Filler , Garth T Whiteside , Mark Bacon , Martyn Frederickson , Franklyn A Howe , Miri D Rabinowitz , Alan J Sokoloff , Terrence W Deacon , Chris Abell , Raj Munglani , John R Griffiths , B ANTHONY Bell and Andrew ML Lever
BMC Neuroscience 2010, 11:8doi:10.1186/1471-2202-11-8, Published: 20 January 2010

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Background

Targeted delivery of pharmaceutical agents into selected populations of CNS neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

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Neurons Developed from Stem Cells Successfully Wired With Other Brain Regions in Animals

ScienceDaily (Jan. 19, 2010) — Transplanted neurons grown from embryonic stem cells can fully integrate into the brains of young animals, according to new research in the Jan. 20 issue of The Journal of Neuroscience.

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Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies

Russell H. Swerdlow
Departments of Neurology and Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, MO, Kansas 66160, USA

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Abstract: Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed.

 

Keywords: mitochondria; mitochondrial biogenesis; mitochondriopathies; neurodegenerative diseases; oxidative stress

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Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology

Citation: Haugen AC, Di Prospero NA, Parker JS, Fannin RD, Chou J, et al. (2010) Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology. PLoS Genet 6(1): e1000812. doi:10.1371/journal.pgen.1000812
Editor: Christopher E. Pearson, The Hospital for Sick Children and University of Toronto, Canada
Received: May 5, 2009; Accepted: December 10, 2009; Published: January 15, 2010
OPEN ACCESS This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Abstract


The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.

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Excess DNA damage found in cells of patients with Friedreich's ataxia. Biomarkers, new treatments possible for Friedreich's ataxia

Genetic Engineering & Biotechnology News, PITTSBURGH, Jan. 14

Autosomal recessive ataxias: 20 types, and counting

Embiruçu EK, Martyn ML, Schlesinger D, Kok F.
Outpatient Neurogenetics Clinic, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, SP, Brazil.

Keywords: Friedreich ataxia, autosomal recessive ataxias, neurogenetics, clinical and pathophysiological aspects,  diagnosis.

Treatment of mitochondrial electron transport chain disorders: A review of clinical trials over the past decade.

Mol Genet Metab. 2009 Nov 26. [Epub ahead of print]

Kerr DS.

Center for Inherited Disorders of Metabolism, University Hospitals Case Medical Center, Rainbow Babies and Childrens Hospital, Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-6004, USA.

Keywords: mitochondrial electron transport chain disorders, controlled clinical trials, dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, neuropathy,  Friedreich ataxia, cardiomyopathy, neurological protection.

Penwest Announces Initiation of Phase IIa Clinical Trial of A0001 in Patients With Friedreich's Ataxia

PATTERSON, N.Y., Jan. 11, 2010 (GLOBE NEWSWIRE)

Measuring the rate of progression in Friedreich ataxia: Implications for clinical trial design

Movement Disorders, Early View (Articles online in advance of print)
Published Online: 8,Jan,2010

 Lisa S. Friedman, BS ^{1 2 3}, Jennifer M. Farmer, MS ^{1 2 3}, Susan Perlman, MD ⁴, George Wilmot, MD, PhD ⁵, Christopher M. Gomez, MD PhD ^{6 7}, Khalaf O. Bushara, MD ⁶, Katherine D. Mathews, MD ⁸, S. H. Subramony, MD ^{9 10}, Tetsuo Ashizawa, MD ^{9 11}, Laura J. Balcer, MD, MSCE ¹, Robert B. Wilson, MD, PhD ¹², David R. Lynch ^{1 2 3 *1}Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
²Department of Pediatrics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
³Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
⁴Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
⁵Department of Neurology, Emory University, Atlanta, Georgia, USA
⁶Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA
⁷Department of Neurology, University of Chicago, Chicago, Illinois, USA
⁸Departments of Neurology and Pediatrics, University of Iowa, Iowa City, Iowa, USA
⁹Department of Neurology, University of Texas Medical Branch, Galveston, Texas, USA
¹⁰Department of Neurology, University of Mississippi, Jackson, Mississippi, USA
¹¹Department of Neurology, University of Florida, Gainesville, Florida, USA
¹²Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Keywords: Friedreich ataxia, natural history study, clinical neurology examination, mitochondrial disorder, trinucleotide repeat disease 

Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin.

Hum Mol Genet. 2010 Jan 6.

Condò I, Malisan F, Guccini I, Serio D, Rufini A, Testi R.

Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Rome.

Keywords: , frataxin,  Friedreich's Ataxia (FRDA),  progressive gait instability, cardiomyopathy, high incidence of diabetes, iron-binding protein,  iron-sulfur clusters (ISC),  iron-chaperone, extramitochondrial pool of mature frataxin, cytosolic aconitase/IRP1, enzymatic and a RNA-binding function,  IRP1 activation.

Stem cells in human neurodegenerative disorders — time for clinical translation?

Clin. Invest. 120(1): 29-40 (2010). doi:10.1172/JCI40543. (January 4, 2010)

Olle Lindvall, Zaal Kokaia

Keywords: Stem cell–based approaches, potential treatments, neurodegenerative disorders, improve function, remyelination, trophic actions,modulation of inflammation.