Neurological diseases remain neglected and ignored

The Lancet, Volume 379, Issue 9813, Page 287, 28 January 2012, doi:10.1016/S0140-6736(12)60123-8

Editorial

"A clinical champion for neurology who will present a national strategy with clear targets, an inbuilt monitoring and data collection system, and priorities for research is urgently needed and long overdue."

Is Friedreich ataxia an epigenetic disorder?

Clinical Epigenetics 2012, 4:2 doi:10.1186/1868-7083-4-2
Published: 30 January 2012 (OPEN ACCESS)

Daman Kumari and Karen Usdin

Abstract (provisional)

Friedreich ataxia (FRDA) is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat number exceeds a critical threshold. In the case of FRDA, the repeat unit is the triplet GAA*TTC and the tandem array is located in the first intron of the FXN gene. Pathology arises because expanded alleles make lower than normal levels of mature FXN mRNA and thus reduced levels of frataxin, the FXN gene product. The repeats form a variety of unusual DNA structures including triplexes. They also form persistent RNA:DNA hybrids in vitro and in bacteria and affect splicing in model systems. More recently the repeats in the FXN gene have also been shown to be enriched for epigenetic marks that are characteristic of transcriptionally repressed regions of the genome. However, exactly how repeats in an intron cause the FXN mRNA deficit in FRDA has been the subject of much debate. Identifying the mechanism or mechanisms responsible for the FXN mRNA deficit in FRDA is important for the development of treatments for this currently incurable disorder. This review discusses evidence for and against possible models for the repeat-mediated mRNA deficit.

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DNA helicase and helicase–nuclease enzymes with a conserved iron–sulfur cluster

Nucl. Acids Res. (2012) doi: 10.1093/nar/gks039 First published online: January 28, 2012 (This article is Open Access)

Yuliang Wu 1 and Robert M. Brosh Jr 2.
1 Department of Biochemistry, University of Saskatchewan, Health Sciences Building, Saskatoon, Saskatchewan, S7N 5E5, Canada
2 Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD 21224, USA

A defect in the synthesis of Fe–S clusters is responsible for mitochondrial dysfunction, leading to nuclear genomic instability (109). Defects in Fe–S assembly due to a deficiency in the iron storage/transport protein frataxin also lead to genomic instability and defective BER (110), suggesting that the conserved Fe–S cluster in Dna2 and other DNA repair/replication proteins may be crippled due to the frataxin deficiency; however, this remains to be shown. Further studies are required to ascertain the importance of the Fe–S staple domain in Dna2 for its nuclear and mitochondrial functions, and the influence of iron homeostasis in this respect.

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Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia

Movement Disorders, Article first published online: 27 JAN 2012 | DOI: 10.1002/mds.24064

Brent L. Fogel, Ji Yong Lee, Jessica Lane, Amanda Wahnich, Sandy Chan, Alden Huang, Greg E. Osborn, Eric Klein, Catherine Mamah, Susan Perlman, Daniel H. Geschwind and Giovanni Coppola

Keywords: cerebellar ataxia, copy number variation, dominant genetic conditions, recessive genetic conditions, spinocerebellar ataxia, adult-onset sporadic ataxia, SCA1, SCA2, SCA3, SCA6, SCA7, Friedreich ataxia.

Iron dysregulation in movement disorders.

Neurobiol Dis. 2012 Jan 12. [Epub ahead of print], http://dx.doi.org/10.1016/j.nbd.2011.12.054,

Petr Dusek a, c, Joseph Jankovic a, Weidong Le b

a Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
b Parkinson's Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
c Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic

Keywords: Iron, neurodegeneration with brain iron accumulation (NBIA), aceruloplasminemia, neuroferritinopathy, Friedreich's ataxia, Parkinson's disease, Huntington's disease, multiple system atrophy, progressive supranuclear palsy.

A 'Disruptive Science' Ready For Commercial Development - Gene Therapy

Mary Ann Liebert, Inc./Genetic Engineering News. (2012, January 26). "A 'Disruptive Science' Ready For Commercial Development - Gene Therapy." Medical News Today.

"The time for commercial development of gene therapy has come. Patients with diseases treatable and curable with gene therapy deserve access to the technology, which has demonstrated both its effectiveness and feasibility"

The promise of induced pluripotent stem cells in research and therapy

Nature 481, 295–305 (19 January 2012), doi:10.1038/nature10761

Daisy A. Robinton & George Q. Daley

Keywords: stem-cell biology, reprogramming technology, pluripotency, somatic cells, personalized regenerative cell therapies.

Supplementary Table (128K)

The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model

Neurobiology of Disease, Available online 20 January 2012, http://dx.doi.org/10.1016/j.nbd.2012.01.002

Vahid Ezzatizadeh a,Ricardo Mouro Pinto b, Chiranjeevi Sandi a, Madhavi Sandi a, Sahar Al-Mahdawi a, Hein te Riele c, Mark A. Pook a.
a Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK
b Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
c Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Keywords: Friedreich ataxia (FRDA), GAA repeat expansion mutation, FXN gene, mismatch repair (MMR) proteins, TNR instability, Msh2, Msh3, Msh6, Pms2,

Oxidative stress induces mitochondrial fragmentation in frataxin-deficient cells

Biochemical and Biophysical Research Communications, Available online 16 January 2012, In Press, Accepted Manuscript. http://dx.doi.org/10.1016/j.bbrc.2012.01.022

Sophie Lefevre a, b, 1, Dominika Sliwa a, 1, Pierre Rustin c, d, Jean-Michel Camadro a, Renata Santos a.
a Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod, CNRS-Université Paris-Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, 75205 Paris cedex 13, France
b ED515 UPMC, 4 place Jussieu 75005 Paris, France
c Inserm, U676, Physiopathology and Therapy of Mitochondrial Disease Laboratory, 75019 Paris, France
d Université Paris-Diderot, Faculté de Médecine Denis Diderot, IFR02, Paris, France

Keywords: Friedreich ataxia (FA), mitochondrial frataxin, iron-sulfur cluster assembly, fragmented mitochondria, oxidative stress, mitochondrial dynamics.

Hippotherapy: An Intervention to Habilitate Balance Deficits in Children With Movement Disorders--A Clinical Trial.

Phys Ther. 2012 Jan 12, Published online before print, doi: 10.2522/​ptj.20110081

Silkwood-Sherer DJ, Killian CB, Long TM, Martin KS.

D.J Silkwood-Sherer, PT, DHS, HPCS, Graduate Program in Physical Therapy, Herbert H. and Grace A. Dow College of Health Professions, 1202 Health Professions Bldg, Central Michigan University, Mt Pleasant, MI 48859 (USA).

Keywords: hippotherapy, children with movement disorders, postural instability, mild to moderate balance problems, Activities Scale for Kids-Performance (ASKp), daily life skills.


Hippotherapy may be a viable treatment strategy for children with mild to moderate balance problems to improve balance deficits and increase performance of daily life skills.

Effects of Friedreich's ataxia GAA repeats on DNA replication in mammalian cells

Nucl. Acids Res. (2012) doi: 10.1093/nar/gks021.

Gurangad S. Chandok 1, Mayank P. Patel 1, Sergei M. Mirkin 2 and Maria M. Krasilnikova
Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA 16802 and 2Department of Biology, Tufts University.

Keyword: Friedreich's ataxia (FRDA),(GAA)n repeat, age-dependent instability, episomal DNA replication, chromatin.

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Reactive Oxygen Species and Aging in Caenorhabditis elegans: Causal or Casual Relationship?

Jeremy Michael Van Raamsdonk and Siegfried Hekimi and. Antioxidants & Redox Signaling. December 15, 2010, 13(12): 1911-1953. doi:10.1089/ars.2010.3215.

Keywords: reactive oxygen species (ROS), aging, Caenorhabditis elegans, frh-1-frataxin

S-Glutathionylation: From Molecular Mechanisms to Health Outcomes

Antioxidants & Redox Signaling. July 1, 2011, 15(1): 233-270. doi:10.1089/ars.2010.3540.

Ying Xiong, Joachim D. Uys, Kenneth D. Tew, and Danyelle M. Townsend.

KEYWORDS: Redox homeostasis, human disease pathologies, glutathione, Friedreich's ataxia

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

Antioxidants & Redox Signaling. null, Vol. 0, No. 0,-Not available-, ahead of print. doi:10.1089/ars.2011.4119.

Elizabeth A. Sabens Liedhegner 1, Xing-Huang Gao 2, and John J. Mieyal 2,3
1Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
2Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
3Louis B. Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio.



Keywords: Neurodegenerative diseases, oxidative stress, reactive oxygen species (ROS), reactive nitrogen species (RNS), glutathione (GSH), Friedreich's ataxia

The European Hospital Exemption Clause—New Option for Gene Therapy?

Human Gene Therapy.
Christian J. Buchholz, Ralf Sanzenbacher, and Silke Schüle. January 2012, 23(1): 7-12. doi:10.1089/hum.2011.2529.

Keywords: Gene-therapy medicinal products, authorized clinical trials, centralized procedure, European Medicines Agency, Regulation (EC) No. 1394/2007, cell-therapy products, hospital exemption, exclusive professional responsibility.

Friedreich-Like Ataxia as an Initial Manifestation of Mitochondrial DNA 8344A>G Mutation.

J Child Neurol. 2012 Jan 12.

Chevallier JA, Koenig MK.
Department of Pediatrics, Division of Child and Adolescent Neurology, University of Texas Health Science Center, Houston, TX, USA.

Keywords: subacute onset of ataxia, acute-onset cardiac and pulmonary failure, Magnetic resonance imaging (MRI),nerve conduction velocities, electromyography, sensorimotor axonal neuropathy, Friedreich ataxia, molecular testing of the frataxin gene, mutation at 8344A>G in transfer RNA lysine.

Iron Intake In Teen Years Can Impact Brain In Later Life

University of California - Los Angeles. (2012, January 13). "Iron Intake In Teen Years Can Impact Brain In Later Life." Medical News Today

"The findings may aid future studies of how iron transport affects brain function, development and the risk of neurodegeneration."

Reference:
Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene. Published online before print January 9, 2012, doi: 10.1073/pnas.1105543109 PNAS January 9, 2012

DEVELOPPEMENT D’UN SCORE DE STABILITE CHEZ LES PERSONNES PRESENTANT DES PATHOLOGIES D’ORIGINE NEUROLOGIQUE ENTRAINANT DES TROUBLES DE LA MARCHE ET/OU DE L’EQUILIBRE

THESE, Pour l’obtention du grade de DOCTEUR DE L’UNIVERSITE PARIS-SUD 11
Arnaud GOUELLE

Soutenue le 13 décembre 2011


CHAPITRE VI - Apport du GVI dans l’évaluation de l’ataxie de Friedreich 155
VI.1 Préambule 155
VI.2 Introduction 157
VI.3 Méthode 158
VI.4 Résultats 160
VI.5 Discussion 163

Movement disorders: Genetic and epigenetic factors determine the clinical course in Friedreich ataxia

Nat Rev Neurol. 2012 Jan 10., doi:10.1038/nrneurol.2011.215

Katie Kingwell

Keywords: Friedreich ataxia (FRDA, GAA repeat expansion, frataxin gene (FXN), DNA methylation.

China stops unapproved stem cell treatments

(Reuters) - BEIJING | Tue Jan 10, 2012

China has ordered a halt to all unapproved stem cell treatments and clinical trials, state media reported on Tuesday, as Beijing seeks to rein in the largely untested stem cell therapies now on offer across the country.

"Health providers could no longer charge money for experimental stem cell applications"

Solving the Structure of a Protein That Shows Promise as a DNA-Targeting Molecule for Gene Correction, Therapy

ScienceDaily, 5 Jan. 2012. Web. 9 Jan. 2012.
Fred Hutchinson Cancer Research Center. "Solving the structure of a protein that shows promise as a DNA-targeting molecule for gene correction, therapy."

ScienceDaily (Jan. 5, 2012) — Researchers at Fred Hutchinson Cancer Research Center have solved the three-dimensional structure of a newly discovered type of gene-targeting protein that has shown to be useful as a DNA-targeting molecule for gene correction, gene therapy and gene modification.

A. N.-S. Mak, P. Bradley, R. A. Cernadas, A. J. Bogdanove, B. L. Stoddard. The Crystal Structure of TAL Effector PthXo1 Bound to Its DNA Target. Science, 2012; DOI: 10.1126/science.1216211

Chromatin changes in the development and pathology of the Fragile X-associated Disorders and Friedreich ataxia

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
In Press, Accepted Manuscript, doi:10.1016/j.bbagrm.2011.12.009

Daman Kumari, Rachel Lokanga, Dmitry Yudkin, Xiao-Nan Zhao, Karen Usdin
Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda

Keywords: The fragile X-associated disorders (FXDs), Friedeich ataxia (FRDA), expansion of a trinucleotide repeat, transcribed but not translated, FXN transcript.

Conference about the research project on Friedreich Ataxia given by Dr. Jacques P.Tremblay

"Development of a potential therapy for Friedreich ataxia"
This research project is directed by Dr. Jacques P. Tremblay, Ph.D., professor in the Department of Molecular Medicine of Laval University in Quebec and main investigator at the Research Centre of Quebec City (CHUL).

New Clinical Trial in Friedreich's Ataxia in Italy

FARA, January 5, 2012 -- The Italian Health Ministry and the Ethics Committee of the San Luigi Hospital in Torino, Italy, have given investigators at the hospital approval to initiate a Phase I clinical trial of a new drug designed specifically to treat Friedreich's ataxia. After additional study site preparations, this Phase I trial will test the Repligen drug, known as RG2833, in patients with Friedreich’s ataxia.

Erythropoietin in friedreich ataxia: No effect on frataxin in a randomized controlled trial

Movement Disorder, Article first published online: 4 JAN 2012 | DOI: 10.1002/mds.24066
Caterina Mariotti, Roberto Fancellu, Serena Caldarazzo, Lorenzo Nanetti, Daniela Di Bella, Massimo Plumari, Giuseppe Lauria, Maria D. Cappellini, Lorena Duca, Alessandra Solari and Franco Taroni

Results: Erythropoietin treatment was safe and well tolerated, but did not result in any significant hematological, clinical, or biochemical effects in Friedreich ataxia patients.

Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target

Nucleic Acids Research, 2012, Vol. 40, No. 1 11–26
doi:10.1093/nar/gkr729

Wlodzimierz J. Krzyzosiak, Krzysztof Sobczak, Marzena Wojciechowska, Agnieszka Fiszer, Agnieszka Mykowska and Piotr Kozlowski.
Laboratory of Cancer Genetics, Institute of Bioorganic Chemistry, Polish Academy of sciences, Noskowskiego, 12/14, 61-704 Poznan, Poland

Over 20 different genes containing unstable TNRs have been implicated in the pathogenesis of human neurological diseases (TREDs) .Expanded CTG, CGG, GAA and CAG repeats are associated with DM1, FXTAS, Friedreich’s ataxia (FRDA) as well as HD and a series of SCAs.

Nechanisms underlying TREDs:
-Toxic RNA gain-of-function caused by transcripts harboring expanded CUG, CAG or CGG repeats
-Toxic protein gain-of-function through expression of polyglutamine (polyQ) tract encoded by mutant CAG repeats
-Aberrant loss-oftranscript and loss-of-protein function caused by GAA (FRDA) and CGG expansions.

Considering the results of the most recent reports one can speculate that the mechanistic complexity of pathogenesis in TREDs is higher and more variable.


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