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.

FULL TEXT PDF

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.

FULL TEXT PDF

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

FULL TEXT PDF

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".../...