Stress signals link pre-existing sickness with susceptibility to bacterial infection

Bio-Medicine, Date:7/28/2009

Mitochondrial diseases disrupt the power generating machinery within cells and increase a person's susceptibility to bacterial infection, particularly in the lungs or respiratory tract.

The First Cellular Models Based on Frataxin Missense Mutations That Reproduce Spontaneously the Defects Associated with Friedreich Ataxia

Open-access -Creative Commons Attribution License
Full text

PLoS One. 2009; 4(7): e6379.
Published online 2009 July 24. doi: 10.1371/journal.pone.0006379.
The First Cellular Models Based on Frataxin Missense Mutations That Reproduce Spontaneously the Defects Associated with Friedreich Ataxia
Nadège Calmels,#1,4,5 Stéphane Schmucker,#1,4,5 Marie Wattenhofer-Donzé,1,5 Alain Martelli,1,5 Nadège Vaucamps,1 Laurence Reutenauer,1,3 Nadia Messaddeq,1,2 Cécile Bouton,6 Michel Koenig,1,2,3,4,5 and Hélène Puccio1,2,3,4,5*
1IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France
2Inserm, U596, Illkirch, France
3CNRS, UMR7104, Illkirch, France
4Université de Strasbourg, Strasbourg, France
5Collège de France, Chaire de génétique humaine, Illkirch, France
6Institut de Chimie des Substance Naturelles, CNRS, Gif-sur-Yvette, France
Ellen A. A. Nollen, Editor
University Medical Center Groningen, Netherlands
#Contributed equally.
* E-mail:hpuccio@igbmc.fr

Conceived and designed the experiments: NC SS HMP. Performed the experiments: NC SS MWD AM NV LR NM CB. Analyzed the data: NC SS HMP. Wrote the paper: NC SS AM MK HMP.
Received May 11, 2009; Accepted June 25, 2009.

ABSTRACT

Background
Friedreich ataxia (FRDA), the most common form of recessive ataxia, is due to reduced levels of frataxin, a highly conserved mitochondrial iron-chaperone involved in iron-sulfur cluster (ISC) biogenesis. Most patients are homozygous for a (GAA)n expansion within the first intron of the frataxin gene. A few patients, either with typical or atypical clinical presentation, are compound heterozygous for the GAA expansion and a micromutation.
Methodology
We have developed a new strategy to generate murine cellular models for FRDA: cell lines carrying a frataxin conditional allele were used in combination with an EGFP-Cre recombinase to create murine cellular models depleted for endogenous frataxin and expressing missense-mutated human frataxin. We showed that complete absence of murine frataxin in fibroblasts inhibits cell division and leads to cell death. This lethal phenotype was rescued through transgenic expression of human wild type as well as mutant (hFXNG130V and hFXNI154F) frataxin. Interestingly, cells expressing the mutated frataxin presented a FRDA-like biochemical phenotype. Though both mutations affected mitochondrial ISC enzymes activities and mitochondria ultrastructure, the hFXNI154F mutant presented a more severe phenotype with affected cytosolic and nuclear ISC enzyme activities, mitochondrial iron accumulation and an increased sensitivity to oxidative stress. The differential phenotype correlates with disease severity observed in FRDA patients.
Conclusions
These new cellular models, which are the first to spontaneously reproduce all the biochemical phenotypes associated with FRDA, are important tools to gain new insights into the in vivo consequences of pathological missense mutations as well as for large-scale pharmacological screening aimed at compensating frataxin deficiency.

Human ISD11 is essential for both iron–sulfur cluster assembly and maintenance of normal cellular iron homeostasis

Human Molecular Genetics Advance Access originally published online on May 18, 2009
Human Molecular Genetics 2009 18(16):3014-3025; doi:10.1093/hmg/ddp239
Published by Oxford University Press 2009

Yanbo Shi, Manik C. Ghosh, Wing-Hang Tong and Tracey A. Rouault^*

National Institute of Child Health and Human Development, Molecular Medicine Program, Bethesda, MD 20892, USA

^* To whom correspondence should be addressed. Tel: +1 301 496 6368; Fax: +1 301 402 0078; Email: trou@helix.nih.gov

Keywords: iron–sulfur (Fe–S) cluster biogenesis, Saccharomyces cerevisiae, cysteine desulfurase (ISCS), mitochondrial compartment, inactivated mitochondrial and cytosolic aconitases, iron regulatory protein 1, iron regulatory protein 2, punctate ferric iron accumulations in cells, iron homeostasis.

Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease (FAIR-PARK-I)

Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease (FAIR-PARK-I)
This study is not yet open for participant recruitment.
Verified by University Hospital, Lille, July 2009
First Received: July 20, 2009 Last Updated: July 21, 2009 History of Changes
Sponsored by:
University Hospital, Lille
Information provided by:
University Hospital, Lille
ClinicalTrials.gov Identifier:
NCT00943748

Transplanted Neurons Develop Disease-like Pathology In Huntington's Patients

ScienceDaily (July 20, 2009) — The results of a recent study published in the Proceedings of the National Academy of Sciences question the long-term effects of transplanted cells in the brains of patients suffering from Huntington's disease.

Other source: http://www.eurekalert.org/pub_releases/2009-07/ul-tnd071609.php

Original work which explains the test:

Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Thomas B. Freeman,^abcde Francesca Cicchetti,^df Robert A. Hauser,^bcg Terrence W. Deacon,^f Xiao-Jiang Li,^h Steven M. Hersch,ⁱ G. Michael Nauert,^j Paul R. Sanberg,^abc Jeffrey H. Kordower,^k Samuel Saporta,^acl and Ole Isacson^ef

^aDepartment of Neurosurgery,^bDepartment of Pharmacology and Experimental Therapeutics, and, ^cThe Neuroscience Program, University of South Florida, Tampa, FL 33606; Departments of, ^gNeurology and, ^lAnatomy,^jWomen's Center, Tampa, FL 33606;^kDepartment of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, IL 60612;^fNeuroregeneration Laboratory, McLean Hospital/MGH, Harvard Medical School, Belmont, MA 62478; and Departments of, ^hGenetics and, ⁱNeurology, Emory University, Atlanta, GA 30322

^dT.B.F. and F.C. contributed equally to this work.

^eTo whom reprint requests should be addressed: T.B.F. (phone: 813-259-0889; fax: 813-259-0944; E-mail: tfreeman@com1.med.usf.edu) or O.I. (E-mail: isacson@helix.mgh.harvard.edu).

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 12, 2000

Received July 13, 2000.

Penwest Announces Results of Phase Ib Trial of A0001

GlobeNewswire
Source: Penwest Pharmaceuticals Co.

In the Phase Ib trial, the drug was well tolerated by subjects, and no serious adverse events were reported. There was a dose-dependent increase in exposure approaching steady state within 2-4 days following repeat-dosing, and a maximum tolerated dose was established.

Plans to Advance A0001 Into Phase IIa Trials in Patients in Second Half of 2009

http://www.penw.com/

http://health.groups.yahoo.com/group/FA_babelFAmily/message/3058

UA Professors receive over $1.45 million in grants

Money to fund researching neurological diseases
The Crimson White, Published: Thursday, July 16, 2009
.../...
While they are researching different topics, both professors are focusing on certain proteins found in the body and their roles in neurological diseases. Busenlehner’s research focuses on a neurodegenerative disease called Friedreich’s ataxia, which is caused by decreased levels of the protein frataxin.
“What we are wanting to know is what is the exact function of this protein, frataxin, in the human body,” Busenlehner said.
.../...

Huntington's: Researchers Gain Insight Into Mechanism Underlying The Disease

Medical News Today , Article Date: 15 Jul 2009 - 0:00 PDT

Researchers at the University of Kentucky Markey Cancer Center and Graduate Center for Toxicology (GCT) have gained new insight into the genetic mechanisms underlying Huntington's disease and other neurodegenerative or neuromuscular disorders caused by trinucleotide repeats (or TNRs) in DNA.



This newspaper article is based on this research: http://friedreichscientificnews.blogspot.com/2009/07/incision-dependent-and-error-free.html

Incision-dependent and error-free repair of (CAG)(n)/(CTG)(n) hairpins in human cell extracts

Nat Struct Mol Biol. 2009 Jul 13

Hou C, Chan NL, Gu L, Li GM.
Graduate Center for Toxicology and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.

Keywords: Expansion of CAG/CTG trinucleotide repeats, neurological disorders, Huntington's disease, proliferating cell nuclear antigen (PCNA), endonuclease activities, trinucleotide repeat instability.

[Diseases caused by triplet expansion.]

Rev Neurol. 2009 Jul 16-31;49(2):79-87

[Article in Spanish]
Rosales-Reynoso MA, Ochoa-Hernandez AB, Barros-Nunez P.
Centro de Investigacion Biomedica de Occidente IMSS (CIBO), Guadalajara, Mexico

Keywords: expansion of nucleotide triplets, meiosis, mitosis, CGG/ GCC, CAG/GTC, CTG/GAC, GAA/CTT, bulbospinal muscular atrophy, Huntington's diseas, spinocerebellar ataxias, fragile X syndrome, Friedreich's ataxia, myotonic dystrophy, cis-acting, trans-acting, pre-mutations, dynamic mutation processes.