Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients

Gene Expression Omnibus, Series GSE11204
Experiment type Expression profiling by array, Public on Dec 08, 2009

Keywords: Friedreich's ataxia; frataxin; mitochondrial DNA damage; nuclear DNA damage; genotoxic stress

A Wireless Brain-Machine Interface for Real-Time Speech Synthesis

"Perhaps the most debilitating aspect of profound paralysis due to accident, stroke, or disease is loss of the ability to speak. The loss of speech not only makes the communication of needs to caregivers very difficult, but it also leads to profound social isolation of the affected individual."


PLoS ONE 4(12): e8218. doi:10.1371/journal.pone.0008218

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Frank H. Guenther1,2*, Jonathan S. Brumberg1,3, E. Joseph Wright3, Alfonso Nieto-Castanon4, Jason A. Tourville1, Mikhail Panko1, Robert Law1, Steven A. Siebert3, Jess L. Bartels3, Dinal S. Andreasen3,5, Princewill Ehirim6, Hui Mao7, Philip R. Kennedy3

1 Department of Cognitive and Neural Systems and Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts, United States of America, 2 Division of Health Sciences and Technology, Harvard University-Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 3 Neural Signals Inc., Duluth, Georgia, United States of America, 4 StatsANC LLC, Buenos Aires, Argentina, 5 Georgia Tech Research Institute, Marietta, Georgia, United States of America, 6 Gwinnett Medical Center, Lawrenceville, Georgia, United States of America, 7 Emory Center for Systems Imaging, Emory University Hospital, Atlanta, Georgia, United States of America

Abstract
Background: Brain-machine interfaces (BMIs) involving electrodes implanted into the human cerebral cortex have recently been developed in an attempt to restore function to profoundly paralyzed individuals. Current BMIs for restoring communication can provide important capabilities via a typing process, but unfortunately they are only capable of slow communication rates. In the current study we use a novel approach to speech restoration in which we decode continuous auditory parameters for a real-time speech synthesizer from neuronal activity in motor cortex during attempted speech.

Methodology/Principal Findings: Neural signals recorded by a Neurotrophic Electrode implanted in a speech-related region of the left precentral gyrus of a human volunteer suffering from locked-in syndrome, characterized by near-total paralysis with spared cognition, were transmitted wirelessly across the scalp and used to drive a speech synthesizer. A Kalman filter-based decoder translated the neural signals generated during attempted speech into continuous parameters for controlling a synthesizer that provided immediate (within 50 ms) auditory feedback of the decoded sound. Accuracy of the volunteer's vowel productions with the synthesizer improved quickly with practice, with a 25% improvement in average hit rate (from 45% to 70%) and 46% decrease in average endpoint error from the first to the last block of a three-vowel task.

Conclusions/Significance: Our results support the feasibility of neural prostheses that may have the potential to provide near-conversational synthetic speech output for individuals with severely impaired speech motor control. They also provide an initial glimpse into the functional properties of neurons in speech motor cortical areas.

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Supplementation with the reduced form of Coenzyme Q10 decelerates phenotypic characteristics of senescence and induces a peroxisome proliferator-activated receptor- gene expression signature in SAMP1 mice

Molecular Nutrition & Food Research
Received: 4 April 2009; Revised: 10 June 2009; Accepted: 30 June 2009.

Constance Schmelzer 1, Hiroshi Kubo 2, Masayuki Mori 3, Jinko Sawashita 3, Mitsuaki Kitano 2, Kazunori Hosoe 4, Inka Boomgaarden 1, Frank Döring 1 *, Keiichi Higuchi 3


1Institute of Human Nutrition and Food Science, Molecular Prevention, Christian-Albrechts-University of Kiel, Kiel, Germany
2Kaneka Corporation, Frontier Biochemical and Medical Research Laboratories, Takasago, Hyogo, Japan
3Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan
4Kaneka Corporation, Functional Food Ingredients Division, Osaka, Japan

Keywords:  CoQ10, gene expression, inflammation, lipid metabolism, peroxisome proliferator-activated receptor- alpha, reduced form (Q10H2) coenzyme Q10 (CoQ10),  liver, heart, brain,  kidney,  stronger impact on gene expression, bioavailability, degenerative processes.

Friedreich Ataxia: An Update on Animal Models, Frataxin Function and Therapies

Advances in experimental medicine and biology,   ISSN 0065-2598  CODEN AEMBAP. 2009, vol. 652, pp. 247-261 [15 page(s) (article)

GONZALEZ-CABO Pilar ; VICENTE LLORENS José ; PALAU Francesc ; MOLTO Maria Dolores ;  

Keywords: Friedreich ataxia ; Frataxin ; Mitochondria ; Iron-sulfur clusters ; Oxidative stress ; Oxidative phosphorylation ; Antioxidant therapy ; Iron chelators ; Recombinant human erythropoietin ; Histone deacetylase inhibitors ;

PGC-1 activation as a therapeutic approach in mitochondrial disease

IUBMB IUBMB Life, 61(11): 1051-1062, 2009

Tina Wenz.
Department of Neurology, University of Miami School of Medicine, Miami, FL 33136, USA

Keywords: Mitochondria,  cellular homeostasis, mitochondrial dysfunction, ATP,  OXPHOS, PGC-1.

Impairment in motor reprogramming in Friedreich ataxia reflecting possible cerebellar dysfunction.

J Neurol. 2009 Dec 3

Corben LA, Delatycki MB, Bradshaw JL, Horne MK, Fahey MC, Churchyard AJ, Georgiou-Karistianis N.

Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, 10th Floor, Flemington Road, Parkville, VIC, 3052, Australia.

Keywords: cerebellar and spinocerebellar dysfunction, Friedreich ataxia (FRDA), motor function, cortical pathology, cerebello-cortical projections, , mov6ement execution, movement preparation, age of onset.

Oxidative Stress Studies in Yeast With a Frataxin Mutant; A Proteomics Perspective

Proteome Res., Just Accepted Manuscript

Publication Date (Web): December 3, 2009

 

Jin-Hee Kim , Miroslav Sedlak , Qiang Gao , Catherine P Riley , Fred Regnier and Jiri Adamec

 

Department of Chemistry, Laboratory of Renewable Resources Engineering, Department of Agricultural and Biological Engineering, Bindley Bioscience Center at Discovery Park, Purdue University, West Lafayette, IN USA 47907

Keywords: Cellular response, Δyfh1 mutant, oxidative stress, iron, mitochondria,  carbonyl groups, reactive oxygen species (ROS), proteomic techniques, protein carbonylation.

 

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Absence of aprataxin gene mutations in a Greek cohort with sporadic early onset ataxia and normal GAA triplets in frataxin gene.

Neurol Sci. 2009 Dec 2.

Daiou C, Christodoulou K, Xiromerisiou G, Panas M, Dardiotis E, Kladi A, Speletas M, Ntaios G, Papadimitriou A, Germenis A, Hadjigeorgiou GM.

Laboratory of Neurogenetics, Neuroscience Unit, Department of Neurology, Faculty of Medicine, University of Thessalia, Larissa, Greece.

Keywords: Phenotype, aprataxin gene mutation,  GAA expansion,  frataxin gene, exons, flanking intronic sequences, cerebellar ataxia, point mutation, Friedreich ataxia.

A neurite quality index and machine vision software for improved quantification of neurodegeneration

BioTechniques, Vol. 47, No. 6, December 2009, pp. iii–viii

Peggy L. Romero1, Ted Miller2, and Arman M. Garakani2
1Sirtris, A GSK Company, Cambridge, MA, USA
2Reify Corporation, Saratoga, CA, USA
 
Keywords: neurodegradation in dorsal root ganglion cultures,  model for neurodegenerative diseases, quantify neuroprotection, neurite quality index (NQI),  neurosight,  vision-based method, SIRT1, resveratrol, nicotinamide adenine dinucleotide (NAD), axons.
 
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Mitochondrial and Nuclear Genes of Mitochondrial Components in Cancer

Curr Genomics. 2009 June; 10(4): 281–293. doi: 10.2174/138920209788488517.

E Kirches*

Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany

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3. OTHER NUCLEAR-ENCODED MITOCHONDRIAL PROTEINS DISCUSSED IN CANCER
3.1. Does Frataxin Play an Inhibiting Role in ROS-Mediated Tumorigenesis ?
Friedreich’s ataxia is a severe neurodegenerative disease of adulthood, often accompanied by cardial hypertrophy and usually leading to the patient’s death within 15 years. It is inherited as a recessive autosomal trait, caused by an intronic GAA trinucleotid expansion in the frataxin gene, which switches off transcription of the affected allele [55]. Frataxin is a mitochondrial protein, which is suggested to be involved in iron homeostasis in the mitochondria, since a reduced amount of the protein in patients with the intragenic trinucleotide expansion leads to intramitochondrial iron deposits. Although the details of frataxin function are currently a matter of debate, these deposits may indicate an insufficient transport of iron to the sites of iron-sulfur cluster biogenesis by frataxin [56-59], which in turn may hamper the incorporation of correctly iron-loaded Fe/S-clusters into various mitochondrial proteins, such as the Fe/S-containing ETC complexes. In cell cultures, frataxin inactivation was shown to result in ETC inhibition, as demonstrated by a diminished mitochondrial membrane potential, decreased O2-consumption and decreased oxidative ATP synthesis. Frataxin dysfunction may lead to an inhibition of mitochondrial energy metabolism. On the other hand, a dysfunction of ETC complexes, as well as deposits of free iron (by Fenton reaction) can cause enhanced generation of ROS in the mitochondrial matrix and in the intermembrane space. Oxidative stress is thought to further damage ETC complexes and other redox-sensitive proteins, such as the Krebs cycle enzyme aconitase. This oxidative stress component may further inhibit intermediary metabolism and oxidative ATP synthesis.

Ristow and colleagues analyzed for the first time a potential tumor suppressing function of frataxin in cell culture and animal models, although patients suffering from Friedreich’s ataxia are in no way prone to a higher tumor burden. The idea behind this work was a potential connection between the antioxidative properties of frataxin and ROS-mediated tumorigenesis. The authors analyzed this topic initially in murine 3T3L1 cells, which had been transfected with either a vector expressing human frataxin or a control construct [60]. Both cell clones were exposed to culture conditions with artificially enhanced ROS production. The cells overexpressing frataxin exhibited a significantly lower number of anchorage-independent foci in the culture dishes and the rate of colony formation in soft agar assays was significantly lower, indicating that frataxin protected the cells from ROS-induced transformation into a tumor phenotype. This was further supported by the observation that only cells from the anchorage-independent foci were able to induce tumor growth when xenografted to nude mice.

While oxidative stress in frataxin-deficient patients with Friedreich’s ataxia may be due to the disturbed synthesis of Fe/S-clusters and mitochondrial iron deposits, it is less obvious as to how enforced overexpression of frataxin in normal cells may protect them against ROS. The authors explained the protective effect by the observed increase in glutathione peroxidase (GPx) activity and in reduced thiols. GPx and the reduced form of glutathione play an important role in the detoxification of H2O2, which is built as a product of the SOD- (superoxide dismutase) reaction. Superoxide dismutase 2 (SOD2) is a mitochondrial enzyme, which detoxifies superoxide radicals, released mainly from ETC complexes I and III into the mitochondrial matrix.

In a next step, the authors investigated the potential tumor suppressing effect of enforced frataxin expression in the colon cancer lines MIP101, DLD2 and HT29, which lack endogenous expression of the protein. Mitochondrial oxidative metabolism was enhanced in the transfected cells, as could be shown by an increase of mitochondrial membrane potential, cellular respiration and ATP content, as well as aconitase activity. Increased aconitase activity may be explained in part by decreased oxidative stress. Again, the frataxin cells exhibited a lower colony formation rate in soft agar essays and a lower rate of tumor growth after xenotransplantation to nude mice [61]. The most direct evidence for a role of frataxin in carcinogenesis was reported by the same group using targeted hepatic disruption of frataxin expression in mice. The animals had reduced life spans and developed multiple hepatic tumors, in which high apoptotic and mitotic (Ki-67) indices were observed [62]. The liver specimen showed elevated levels of thiobarbituric-acid reactive substances (TBARS), a marker of lipid peroxidation, and elevated levels of oxidized glutathione, a classical oxidative stress marker. Activities of those mitochondrial enzymes, which contain Fe/S-moieties, i.e. aconitase and ETC complexes I, II, III, were reduced. In accordance with an inhibited oxidative metabolism, the ATP content of livers from knock-out animals was decreased.

The authors did not develop a detailed hypothesis regarding the mechanism of liver tumorigenesis, but speculated that an observed reduction in p38-MAP-kinase phosphorylation may play a role, since activation of this type of mitogen activated protein kinase had been discussed earlier as a factor suppressing the formation of hepatic tumors [63, 64]. Although the authors did not discuss this issue, it might be speculated, whether the observed inhibition of SDH (complex II) may participate in tumorigenesis.
 
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