OPEN ACCES

PLoS ONE, Full text

Fine Mapping of Gene Regions Regulating Neurodegeneration

Maria Swanberg^1,2, Karin Harnesk^1#, Mikael Ström^1#, Margarita Diez¹, Olle Lidman¹, Fredrik Piehl^1*

1 Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden, 2 Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden

Abstract

Background

Damage to nerve cells and axons leading to neurodegeneration is a characteristic feature of many neurological diseases. The degree of genetic influence on susceptibility to axotomy-induced neuronal death has so far been unknown. We have examined two gene regions, Vra1 and Vra2, previously linked to nerve cell loss after ventral root avulsion in a rat F2 intercross between the DA and PVG inbred rat strains.

Methodology/Principal Findings

In this study, we use two generations (G8 and G10 cohorts) of an advanced intercross line between DA and PVG^av1 to reproduce linkage to Vra1 and to fine-map this region. By isolating the effect from Vra1 in congenic strains, we demonstrate that Vra1 significantly regulates the loss of motoneurons after avulsion. The regulatory effect mediated by Vra1 thus resides in a congenic fragment of 9 megabases. Furthermore, we have used the advanced intercross lines to give more support to Vra2, originally detected as a suggestive QTL.

Conclusions/Significance

The results demonstrated here show that naturally occurring allelic variations affect susceptibility to axotomy-induced nerve cell death. Vra1 and Vra2 represent the first quantitative trait loci regulating this phenotype that are characterized and fine mapped in an advanced intercross line. In addition, congenic strains provide experimental evidence for the Vra1 effect on the extent of injury-induced neurodegeneration. Identification of the underlying genetic variations will increase our understanding of the regulation and mechanisms of neurodegeneration.

Citation: Swanberg M, Harnesk K, Ström M, Diez M, Lidman O, et al. (2009) Fine Mapping of Gene Regions Regulating Neurodegeneration. PLoS ONE 4(6): e5906. doi:10.1371/journal.pone.0005906

Editor: Rafael Linden, Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Biofísica da UFRJ, Brazil

Received: March 19, 2009; Accepted: May 19, 2009; Published: June 15, 2009

Copyright: © 2009 Swanberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the 6th Framework Program of the European Union, NeuroproMiSe, LSHM-CT-2005-018637 and EURATools, LSHG-CT-2005019015, the Swedish Research Council, Wadsworth Foundation, the Swedish Society for Medical Research, the Swedish Brain Foundation, the Nils and Bibbi Jenssens Foundation, the Montel Williams MS Foundation, the GV80 Foundation, the Soderberg Foundation, and the Swedish Association of Persons with Neurological Disabilities. The funders had no role in study design, data collection or analysis, manuscript preparation or decision to publish.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: fredrik.piehl@ki.se

# These authors contributed equally to this work.

Two Signals -- From Within And Out Of Cell -- Specify Motor Neuron Differentiation

ScienceDaily (June 10, 2009) -Science News

Two Signals -- From Within And Out Of Cell -- Specify Motor Neuron Differentiation

ScienceDaily (June 10, 2009) — Two signals – an external one from retinoic acid and an internal one from the transcription factor Neurogenin2 – cooperate to activate chromatin (the basic material of chromosomes) and help determine that certain nerve progenitor cells become motor neurons, said researchers from Baylor College of Medicine in a report in the current issue of the journal Neuron.

Full text: http://www.sciencedaily.com/releases/2009/06/090610124411.htm

Keywords: motor neurons , stem cells, Neurogenin2, retinoic acid , histone acetyltransferase , histones , transcription , nerve progenitor cells, muscular dystrophies

Oligomeric yeast frataxin drives assembly of core machinery for mitochondrial iron-sulfur cluster synthesis.

J Biol Chem. 2009 Jun 2.

Oligomeric yeast frataxin drives assembly of core machinery for mitochondrial iron-sulfur cluster synthesis.

Li H, Gakh O, Smith DY 4th, Isaya G.

Mayo Clinic, College of Medicine, United States.

Mitochondrial biosynthesis of iron-sulfur clusters (ISC)(1) is a vital process involving the delivery of elemental iron and sulfur to a scaffold protein .....

Keywords: iron-sulfur clusters, iron, sulfur, Yfh1, Nfs1-Isd11, Isu1, oligomerization, oxidation, mechanism, mitochondrial ISC synthesis..

Neural stem cell boosting chemical that generate new neurons - received U.S. patent allowance

"Stem Cell Research Blog" 06 Jun 2009 12:43 pm

Neural-stem-cell-boosting-chemical-that-generate-new-neurons-received-us-patent-allowance

The U.S. Patent and Trademark Office (USPTO) have delivered a notice of allowance to Neuralstem, Inc. for a patent on four new chemicals that can boost the generation of new neurons. .....

Keywords: Neuralstem Inc, patent, neurons, neurogenic activity, drugs, human neural stem cells, hippocampus.

Subjective Improvement in Proprioception in 2 Patients With Atypical Friedreich Ataxia Treated With Varenicline (Chantix)

Journal of Clinical Neuromuscular Disease:
June 2009 - Volume 10 - Issue 4 - pp 191-193
doi: 10.1097/CND.0b013e3181910074

Subjective Improvement in Proprioception in 2 Patients With Atypical Friedreich Ataxia Treated With Varenicline (Chantix)
Zesiewicz, Theresa A MD, FAAN; Sullivan, Kelly L MSPH; Gooch, Clifton L MD; Lynch, David R MD, PhD

Keywords: Friedreich ataxia , proprioceptive improvements , varenicline (Chantix), smoking cessation.

Medical News Today: Article Date: 04 Jun 2009 - 7:00 PDT
Source: Nancy Ross-Flanigan. University of Michigan

Small Molecules Mimic Natural Gene Regulators

In the quest for new approaches to treating and preventing disease, one appealing route involves turning genes .......

.../...
These molecules can help scientists probe the transcription process and perhaps eventually be used to correct diseases that result from errors in gene regulation.
.../...

Keywords: turning genes, cancer, diabetes, gene expression, transcriptional activators , CBP.

Original work:( http://pubs.acs.org/doi/abs/10.1021/cb900028j?prevSearch=David+Wemmer&searchHistoryKey= )

Amphipathic Small Molecules Mimic the Binding Mode and Function of Endogenous Transcription Factors

Sara J. Buhrlage†, Caleb A. Bates‡, Steven P. Rowe†, Aaron R. Minter†, Brian B. Brennan†, Chinmay Y. Majmudar†, David E. Wemmer§, Hashim Al-Hashimi† and Anna K. Mapp†‡¶*

† Department of Chemistry ‡ Department of Medicinal Chemistry Department of Biophysics ¶ Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, 48109 § Department of Chemistry, University of California, Berkeley, California 94720

ACS Chem. Biol., 2009, 4 (5), pp 335–344

DOI: 10.1021/cb900028j

Publication Date (Web): April 6, 2009

Copyright © 2009 American Chemical Society

Friedreich ataxia (fa) associated with diabetes mellitus type 1 and hyperthrophic cardiomyopathy.

Friedreich ataxia (fa) associated with diabetes mellitus type 1 and hyperthrophic cardiomyopathy.

Bosn J Basic Med Sci. 2009 May;9(2):107-10.

Gucev Z, Tasic V, Jancevska A, Popjordanova N, Koceva S, Kuturec M, Sabolic V.
Faculty of Medicine Skopje, St. Cyril and Methodius University, 50 Divizija BB, 1000 Skopje, Macedonia.

Progressive signs of ataxia in a eight years old girl prompted neurological investigation. The girl had unstable gait .....

Keywords: Friedreich ataxia, dysarthria, pes cavus, positive Babinski sign, scoliosis, diabetic ketoacidosis, GAA trinucleotide repeat, sinus bradycardia, hyperthrophic cardiomyopathy, beta blocker, insulin.

Prospects for introducing deferiprone as potent pharmaceutical antioxidant.

Prospects for introducing deferiprone as potent pharmaceutical antioxidant.

Front Biosci (Elite Ed). 2009 Jun 1;1:161-178.

Kontoghiorghes GJ.
Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus.

Free radical formation is primarily initiated from metal catalytic centers involving iron and copper. Under certain conditions, free radical reactions .......

Keywords: Free radical, iron, copper, oxidative stress, antioxidants, chelators, Deferiprone, cardiomyopathy, thalassaemia, Friedreich ataxia.

Iron-Sulfur (Fe/S) Protein Biogenesis: Phylogenomic and Genetic Studies of A-Type Carriers

OPEN ACCESS

Source: PLoS-GENETICS, http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000497 (full text)

Iron-Sulfur (Fe/S) Protein Biogenesis: Phylogenomic and Genetic Studies of A-Type Carriers

Daniel Vinella1,2, Céline Brochier-Armanet1,2, Laurent Loiseau1,2, Emmanuel Talla1,2, Frédéric Barras1,2*
1 Laboratoire de Chimie Bactérienne, Institut Fédératif de Recherche 88 - Institut de Microbiologie de la Méditerranée, Centre National de la Recherche Scientifique, Marseille, France, 2 Aix-Marseille Université, Marseille, France

Abstract Top
Iron sulfur (Fe/S) proteins are ubiquitous and participate in multiple biological processes, from photosynthesis to DNA repair. Iron and sulfur are highly reactive chemical species, and the mechanisms allowing the multiprotein systems ISC and SUF to assist Fe/S cluster formation in vivo have attracted considerable attention. Here, A-Type components of these systems (ATCs for A-Type Carriers) are studied by phylogenomic and genetic analyses. ATCs that have emerged in the last common ancestor of bacteria were conserved in most bacteria and were acquired by eukaryotes and few archaea via horizontal gene transfers. Many bacteria contain multiple ATCs, as a result of gene duplication and/or horizontal gene transfer events. Based on evolutionary considerations, we could define three subfamilies: ATC-I, -II and -III. Escherichia coli, which has one ATC-I (ErpA) and two ATC-IIs (IscA and SufA), was used as a model to investigate functional redundancy between ATCs in vivo. Genetic analyses revealed that, under aerobiosis, E. coli IscA and SufA are functionally redundant carriers, as both are potentially able to receive an Fe/S cluster from IscU or the SufBCD complex and transfer it to ErpA. In contrast, under anaerobiosis, redundancy occurs between ErpA and IscA, which are both potentially able to receive Fe/S clusters from IscU and transfer them to an apotarget. Our combined phylogenomic and genetic study indicates that ATCs play a crucial role in conveying ready-made Fe/S clusters from components of the biogenesis systems to apotargets. We propose a model wherein the conserved biochemical function of ATCs provides multiple paths for supplying Fe/S clusters to apotargets. This model predicts the occurrence of a dynamic network, the structure and composition of which vary with the growth conditions. As an illustration, we depict three ways for a given protein to be matured, which appears to be dependent on the demand for Fe/S biogenesis.

Author Summary Top
Iron sulfur (Fe/S) proteins are found in all living organisms where they participate in a wide array of biological processes. Accordingly, genetic defects in Fe/S biogenesis yield pleiotropic phenotypes in bacteria and several syndromes in humans. Multiprotein systems that assist Fe/S cluster formation and insertion into apoproteins have been identified. Most systems include so-called A-type proteins (which we refer to as ATC proteins hereafter), which have an undefined role in Fe/S biogenesis. Phylogenomic analyses presented, here, reveal that the ATC gene is ancient, that it was already present in the last common ancestor of bacteria, and that it subsequently spread to eukaryotes via mitochondria or chloroplastic endosymbioses and to a few archaea via horizontal gene transfers. Proteobacteria are unusual in having multiple ATCs. We show by a genetic approach that the three ATC proteins of E. coli are potentially interchangeable, but that redundancy is limited in vivo, either because of gene expression control or because of inefficient Fe/S transfers between ATCs and other components within the Fe/S biogenesis pathway. The combined phylogenomic and genetic approaches allow us to propose that multiple ATCs enable E. coli to diversify the ways for conveying ready-made Fe/S clusters from components of the biogenesis systems to apotargets, and that environmental conditions influence which pathway is used.
Citation: Vinella D, Brochier-Armanet C, Loiseau L, Talla E, Barras F (2009) Iron-Sulfur (Fe/S) Protein Biogenesis: Phylogenomic and Genetic Studies of A-Type Carriers. PLoS Genet 5(5): e1000497. doi:10.1371/journal.pgen.1000497
Editor: William F. Burkholder, Stanford University, United States of America
Received: December 1, 2008; Accepted: April 28, 2009; Published: May 29, 2009
Copyright: © 2009 Vinella et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by Centre National de la Recherche Scientifique, Université de la Méditerranée, Agence Nationale de la Recherche, Programme Blanc CSD 8 and a CNRS ATIP grant to CB-A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: barras@ifr88.cnrs-mrs.fr

Multiple Sclerosis Patients Benefit From Diabetes Drug

A drug currently FDA-approved for use in diabetes shows some protective effects in the brains of patients with relapsing remitting multiple sclerosis, researchers at the University of Illinois at Chicago College of Medicine report in a study currently available online in the Journal of Neuroimmunology.

Keywords: University of Illinois, pioglitazone, Actos, neuronal survival, clinical trial.

Source Medical News Today
Full text Link: http://www.medicalnewstoday.com/articles/151448.php

Note: Currently in France is running a clinical trial with Pioglitazone for patients with FA.
( http://www.clinicaltrials.gov/ct2/show/NCT00811681?term=friedreich )