Excess iron and Friedreich’s ataxia

LifeScientist

Graeme O'Neill 28/08/2008 13:40:00


While Friedreich’s ataxia is a rare disorder, tracking down the role of the protein implicated in the disease has opened up new therapeutic potentials.

Keywords: free radicals, Friedreich's ataxia, Martin Delatycki, Murdoch Childrens Research Institute, iron chelators, Australia, antioxidants, clinical trials, Friedreich’s Ataxia Research Association (Australasia).

What Is Ataxia? What Causes Ataxia?

Article Date: 31 Aug 2009 - 0:00 PDT
Medical News Today .

Journalistic article written by Christian Nordqvist, make a simple revision of the ataxias, but fine.

MRI methods can show bone marrow stem cells’ viability as brain-repairing therapy

Stem Cell Research Blog, 20 Aug 2009

WASHINGTON - Researchers at Tel Aviv University have offered new hope for people with incurable neurodegenerative diseases like Huntington’s, Alzheimer’s, and Parkinson’s by showing that the viability of stem cells created from a patient’s own bone marrow can be determined using MRI tracking methods.

The role of iron in mitochondrial function.

Biochim Biophys Acta. 2009 Jul;1790(7):629-36. Epub 2008 Oct 7.

Levi S, Rovida E.Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milano, Italy. levi.sonia@hsr.it

Limitations in a frataxin knockdown cell model for Friedreich ataxia in a high-throughput drug screen

OPEN ACCESS

Nadege Calmels , Herve Seznec , Pascal Villa , Laurence Reutenauer , Marcel Hibert , Jacques Haiech , Pierre Rustin , Michel Koenig and Helene Puccio
BMC Neurology 2009, 9:46doi:10.1186/1471-2377-9-46
Published:
24 August 2009

Abstract (provisional)

Pharmacological high-throughput screening (HTS) represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA). FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC) proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay.
Methods
Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA.
Results
The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model.
Conclusions
Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive HTS in the future.

FULL TEXT: http://www.biomedcentral.com/content/pdf/1471-2377-9-46.pdf

M.P.1.02 SNT-MC17/idebenone in the treatment of Friedreich’s ataxia: Preliminary safety data from a 12-month European randomized, placebo-controlled s

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T9T-4WWHRS8-F&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=0027bdaeef768126216c15a42f58f113

M.P.1.02 SNT-MC17/idebenone in the treatment of Friedreich’s ataxia: Preliminary safety data from a 12-month European randomized, placebo-controlled study


J.B. Schulz1, T. Meier2 and G.L. Holder2
1University Medical Center, RWTH Aachen, Department of Neurology, Aachen, Germany
2Santhera Pharmaceuticals (Switzerland) Ltd., Liestal, Switzerland

Frataxin deficiency induces schwann cell inflammation and death.

Biochim Biophys Acta. 2009 Aug 10


Lu C, Schoenfeld R, Shan Y, Tsai C, Hammock B, Cortopassi G.

Department of Molecular Biosciences, University of California, Davis, California, 95616.

The Interaction of Mitochondrial Iron with Manganese Superoxide Dismutase*

J. Biol. Chem., Vol. 284, Issue 34, 22633-22640, August 21, 2009

Amornrat Naranuntarat¹, Laran T. Jensen, Samuel Pazicni, James E. Penner-Hahn, and Valeria C. Culotta²

From the From the Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205 and , the Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109

Keywords: Superoxide dismutase 2 (SOD2), mitochondrial enzymes, manganese, iron, iron-sulfur cluster biogenesis, Isu proteins.

Related Topic:

"Manganese Is the Link between Frataxin and Iron-Sulfur Deficiency in the Yeast Model of Friedreich Ataxia",

Verónica Irazusta, Elisa Cabiscol, Gemma Reverter-Branchat, , Joaquim Ros², and Jordi Tamarit

From the Grup de Bioquímica de l'Estrés Oxidatiu, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, 25008 Lleida, Spai.

J. Biol. Chem., Vol. 281, Issue 18, 12227-12232, May 5, 2006

FDA Clarifies Access to Investigational Drugs

By Cole Petrochko, Staff Writer, MedPage Today
Published: August 13, 2009

WASHINGTON -- The FDA has issued two final rules expanding access to investigational drugs for seriously ill patients who have no alternatives and regulating drug developers' charges for those medicines.

Mitochondrial Dysfunction Leads to Nuclear Genome Instability via an Iron-Sulfur Cluster Defect

Comment: Although in the FA we have not problems with the mtDNA, the genetic information of frataxin is in nDNA, this is a very interesting article.

Cell, Volume 137, Issue 7, 26 June 2009, Pages 1247-1258

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10D8-J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=978708264&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8d80ad217bf0eefe71a1bba6364c95a


Joshua R. Veatch1, 2, Michael A. McMurray1, 2, 3, Zara W. Nelson1 and Daniel E. Gottschling1, ,
1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA
2The Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA
3Present address: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA

Keywords: mitochondrial genome (mtDNA), inestability of the nuclear genome, defect in iron-sulfur cluster (ISC) biogenesis, ISC protein biogenesis.

Cardiac involvement in Friedreich's ataxia: our experience.

Minerva Cardioangiol. 2009 Apr;57(2):269-70.

Fazio G., Vitello D., D’Angelo L., Visconti C., Trapani R., Fabiano A., Di Gesaro G., Novo G., Novo S.

Not abstrac

Nitrative and Oxidative Stress in Toxicology and Disease

OPEN ACCESS

ToxSci Advance Access published online on August 5, 2009 Toxicological Sciences, doi:10.1093/toxsci/kfp179

Ruth A. Roberts1, Debra L. Laskin2, Charles V. Smith3, Fredika M. Robertson4, Erin M.G. Allen5, Jonathan A. Doorn5 and William Slikker6
1 AstraZeneca R&D Safety Assessment, Alderley Park, UK 2 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 3 Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 4 Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 5 College of Pharmacy, University of Iowa, Iowa City, IA 6 NCTR, USFDA, Jefferson, AR
ruth.roberts@astrazeneca.com


Received June 15, 2009; revision received July 22, 2009; accepted July 24, 2009

Abstract

Persistent inflammation and the generation of reactive oxygen and nitrogen species play pivotal roles in tissue injury during disease pathogenesis and as a reaction to toxicant exposures. The associated oxidative and nitrative stress promote diverse pathologic reactions including neurodegenerative disorders, atherosclerosis, chronic inflammation, cancer, and premature labor and stillbirth. These effects occur via sustained inflammation, cellular proliferation and cytotoxicity and via induction of a proangiogenic environment. For example, exposure to the ubiquitous air pollutant ozone leads to generation of reactive oxygen and nitrogen species in lung macrophages that play a key role in subsequent tissue damage. Similarly, studies indicate that genes involved in regulating oxidative stress are altered by anesthetic treatment resulting in brain injury, most notable during development. In addition to a role in tissue injury in the brain, inflammation and oxidative stress are implicated in Parkinson's disease, a neurodegenerative disease characterized by the loss of dopamine neurons. Recent data suggest a mechanistic link between oxidative stress and elevated levels of DOPAL, a neurotoxin endogenous to dopamine neurons. These findings have significant implications for development of therapeutics and identification of novel biomarkers for PD pathogenesis. Oxidative and nitrative stress is also thought to play a role in creating the pro-inflammatory microenvironment associated with the aggressive phenotype of inflammatory breast cancer. An understanding of fundamental concepts of oxidative and nitrative stress can underpin a rational plan of treatment for diseases and toxicities associated with excessive production of reactive oxygen and nitrogen species.

© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgThe online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Full text: http://toxsci.oxfordjournals.org/cgi/reprint/kfp179v1

Vision based interface system for hands free control of an intelligent wheelchair

Open Access

Jin Sun Ju , Yunhee Shin and Eun Yi Kim
Journal of NeuroEngineering and Rehabilitation 2009, 6:33doi:10.1186/1743-0003-6-33
Published: 6 August 2009

Abstract (provisional)
Due to the shift of the age structure in today's populations, the necessities for developing the devices or technologies to support them have been increasing. Traditionally, the wheelchair, including powered and manual ones, is the most popular and important rehabilitation assistive device for the disabled and the elderly. However, it is still highly restricted especially for severely disabled. As a solution to this, the Intelligent Wheelchairs have received considerable attention as mobility aids. The purpose of this work is to develop the IW interface for providing more convenient and efficient interface to the people the disability in their limbs. This paper proposes an intelligent wheelchair control system for the people with various disabilities. To facilitate a wide variety of user abilities, the proposed system involves the use of face-inclination and mouth-shape information, where the direction of an IW is determined by the inclination of the user's face, while proceeding and stopping are determined by the shapes of the user's mouth. Our system is composed of electric powered wheelchair, data acquisition board, ultrasonic infra-red sensors, a PC camera, and vision system. Then the vision system to analyze user's gestures is performed by three stages: detector, recognizer, and converter. In the detector, the facial region of the intended user is first obtained using Adaboost, thereafter the mouth region is detected based on edge information. The extracted features are sent to the recognizer, which recognizes the face inclination and mouth shape using statistical analysis and K-means clustering, respectively. These recognition results are then delivered to the converter to control the wheelchair. The advantages of the proposed system include 1) accurate recognition of user's intention with minimal user motion and 2) robustness to a cluttered background and the time-varying illumination. To prove these advantages, the proposed system was tested with 34 users in indoor and outdoor environments and the results were compared with those of other systems, then the results showed that the proposed system has superior performance to other systems in terms of speed and accuracy. Therefore, it is proved that proposed system provided a friendly and convenient interface to the severely disabled peo


Full text: http://www.jneuroengrehab.com/content/pdf/1743-0003-6-33.pdf

Ataxias with autosomal, X-chromosomal or maternal inheritance.

Can J Neurol Sci. 2009 Jul;36(4):409-28.

Finsterer J.

Krankenanstalt Rudolfstiftung, Vienna, Austria, Europe.

Keywors: Heredoataxias, genetic disorders, cerebellar syndrome, inheritance, autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias, Friedreich ataxia.

New clues about vitamin D functions in the nervous system

by: E. Garcion, N. Wionbarbot, C. Monteromenei, F. Berger, D. Wion
Trends in Endocrinology and Metabolism, Vol. 13, No. 3. (01 April 2002), pp. 100-105.

Keywords: 1α,25 dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], brain function, nuclear receptor, neurons, glial cells, neurotrophic factors, neurotransmitter synthesis, nitric oxide synthase, increase glutathione levels, brain detoxification pathways, neuroprotective, immunomodulatory effects, neurodegenerative diseases, neuroimmune diseases, glioma cell death, brain tumors.

Other link: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3K-45BCJ53-7&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=36fe7df09fbacd4b33fe816072a1793d

Abnormal Brain Circuits May Prevent Movement Disorder

ScienceDaily (Aug. 4, 2009)
.../...
Standaert says that although dystonia is a relatively rare disorder, the study has implications for other neurological illnesses, such as Parkinson's, Alzheimer's, and Huntington's diseases; ataxia and muscular dystrophies; and even forms of migraine.
.../...

Source: The Journal of Neuroscience, August 5, 2009, 29(31):9740-9747; doi:10.1523/JNEUROSCI.2300-09.2009

Cerebellothalamocortical Connectivity Regulates Penetrance in Dystonia

Miklos Argyelan,^{1 *} Maren Carbon,^{1,2,3 *} Martin Niethammer,^1,2,3 Aziz M. Ulu,¹ Henning U. Voss,⁴ Susan B. Bressman,⁵ Vijay Dhawan,^1,2,3 and David Eidelberg^1,2,3

¹Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, Departments of ²Neurology and ³Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, New York 11030, ⁴Department of Radiology, Weill Cornell Medical College, New York, New York 10065, and ⁵Mirken Department of Neurology, Beth Israel Medical Center, New York, New York 10003

Deficiency in frataxin homologue YFH1 in the yeast Pichia guilliermondii leads to missregulation of iron acquisition and riboflavin biosynthesis and a

Biometals. 2009 Aug 1.

Deficiency in frataxin homologue YFH1 in the yeast Pichia guilliermondii leads to missregulation of iron acquisition and riboflavin biosynthesis and affects sulfate assimilation.

Pynyaha YV, Boretsky YR, Fedorovych DV, Fayura LR, Levkiv AI, Ubiyvovk VM, Protchenko OV, Philpott CC, Sibirny AA.

Institute of Cell Biology, NAS of Ukraine, Drahomanov Street 14/16, 79005, Lviv, Ukraine.

Keyword: riboflavin, YFH1, frataxin homologue, iron, impaired sulfate assimilation, hypersensitivity to hydrogen peroxide, superoxide dismutase.

Frataxin, an iron taxi on the road to cellular Fe–S bioassembly

Traffic and storage of metal ions, J Biol Inorg Chem (2009) 14 (Suppl 1):S53–S56 (Oral Presentation)
G-08
Frataxin, an iron taxi on the road to cellular Fe–S bioassembly
Timothy L. Stemmler
Department of Biochemistry and Molecular Biology, Wayne State
University, School of Medicine, Detroit, MI 48201 USA.
tstemmle@med.wayne.edu

http://www.springerlink.com/content/8x412685h746427g/fulltext.pdf

Keywords: Friedreich’s ataxia, iron homeostasis, iron overload, oxidative stress, mitochondrial DNA stability, iron–sulfur protein, iron chaperone, acidic residues, Fe–S cluster assembly enzyme (Isu),