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.


Full text PDF

Changes in mitochondrial glutathione levels and protein thiol oxidation in ∆yfh1 yeast cells and the lymphoblasts of patients with Friedreich's ataxia.

Biochim Biophys Acta. 2011 Nov 11;1822(2):212-225

Bulteau AL, Planamente S, Jornea L, Dur A, Lesuisse E, Camadro JM, Auchère F.
CRICM-INSERM-UMRS975, CNRS UMR 7225-UPMC, Hôpital de la Salpétrière, Physiopathologie cellulaire et moléculaire des maladies mitochondriales, 91, bd de l'hôpital, salle 336, 75651 Paris Cedex 13, France.

Keywords: Friedreich's ataxia (FRDA), frataxin, iron, iron-sulfur cluster, oxidative stress, glutathione homeostasis, protein thiols, GSH/GSSG ratio, aconitase, KGDH.

Small Molecules Mimicking Key Brain Growth Factor Identified By Study

Stanford University Medical Center.

The patents for these four compounds are held by the University of North Carolina and UCSF, where Longo worked before coming to Stanford. While at UNC, Longo founded PharmatrophiX, a company focused on the commercial development of small molecules similar to and including those identified in this study.

Related to: The neurotrophic factor BDNF reduces neurodegeneration induced by frataxin deficiency in neuronal cultures.

DEFINITION OF THE LANDSCAPE OF CHROMATIN STRUCTURE AT THE FRATAXIN GENE IN FRIEDREICH’S ATAXIA

UT GSBS Dissertations and Theses, 12/2011

Keywords: Epigenetics, Chromatin Structure, Histone Modification, Frataxin, FRDA, Neurodegenerative Disease, Repetitive DNA, Triplet repeat, Repeat Diseases

Full text PDF

Orphan designation interferon gamma for the treatment of Friedreich’s ataxia.

On 9 December 2011, orphan designation (EU/3/11/935) was granted by the European Commission to Prof. Roberto Testi, Italy, for interferon gamma for the treatment of Friedreich’s ataxia.

Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: Comparison with studies in muscle biopsy

Molecular Genetics and Metabolism, In Press, Corrected Proof, doi:10.1016/j.ymgme.2011.11.193

Michael J. Goldenthal a, b, Teddy Kuruvilla b, Shirish Damle b, Leon Salganicoff b, Sudip Sheth b, Nidhi Shah b, Harold Marks a, b, Divya Khurana a, Ignacio Valencia a, Agustin Legido a.

a Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA 19134, USA
b Mitochondrial Disease Laboratory, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA 19134, USA

Keywors: Respiratory chain, Mitochondrial disease, Buccal swab, biopsied skeletal muscle, mitochondrial enzyme activities, Buccal citrate synthase, mitochondrial frataxin levels, relatively high correlation (over 82%), non-invasive.