PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

PLoS ONE 5(4): e10025. doi:10.1371/journal.pone.0010025
Daniele Marmolino1, Mario Manto1,2, Fabio Acquaviva3, Paola Vergara3, Ajay Ravella1, Antonella Monticelli4, Massimo Pandolfo1*

1 Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), Brussels, Belgium, 2 Fonds National de la Recherche Scientifique (FNRS), Brussels, Belgium, 3 Department of Cellular and Molecular Biology, University of Naples “Federico II”, Naples, Italy, 4 IEOS, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy

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Background

Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Coactivator 1-alpha (PGC-1α), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models.
Methodology/Principal Findings

We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1α. Compared to control cells, PGC-1α and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1α direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1α activation with the PPARγ agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord.
Conclusions/Significance

PGC-1α down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARγ agonists, suggesting a potential therapeutic approach for FRDA.

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CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy

Published in Volume 120, Issue 4 (April 1, 2010)
J Clin Invest. 2010;120(4):1253–1264. doi:10.1172/JCI41615.

Marco A. Passini, Jie Bu, Eric M. Roskelley, Amy M. Richards, S. Pablo Sardi, Catherine R. O’Riordan, Katherine W. Klinger, Lamya S. Shihabuddin and Seng H. Cheng

Genzyme Corporation, Framingham, Massachusetts.

A New Myohaptic Instrument to Assess Wrist Motion Dynamically

Sensors 2010, 10, 3180-3194; doi:10.3390/s100403180

Mario Manto 1, Niels Van Den Braber 2, Giuliana Grimaldi 3 and Piet Lammertse 2
1  FNRS, Neurologie ULB-Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium
2  Moog FCS, 2150 Ad Nieuw-Vennep, The Netherlands;
3  Neurologie, ULB Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium;


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Abstract: The pathophysiological assessment of joint properties and voluntary motion in neurological patients remains a challenge. This is typically the case in cerebellar patients, who exhibit dysmetric movements due to the dysfunction of cerebellar circuitry. Several tools have been developed, but so far most of these tools have remained confined to laboratories, with a lack of standardization. We report on a new device which combines the use of electromyographic (EMG) sensors with haptic technology for the dynamic investigation of wrist properties. The instrument is composed of a drivetrain, a haptic controller and a signal acquisition unit. Angular accuracy is 0.00611 rad, nominal torque is 6 N·m, maximal rotation velocity is 34.907 rad/sec, with a range of motion of –1.0472 to +1.0472 rad. The inertia of the motor and handgrip is 0.004 kg·m2. This is the first standardized myohaptic instrument allowing the dynamic characterization of wrist properties, including under the condition of artificial damping. We show that cerebellar patients are unable to adapt EMG activities when faced with an increase in damping while performing fast reversal movements. The instrument allows the extraction of an electrophysiological signature of a cerebellar deficit.

Keywords: movement; sensor; myohaptic; damping; ataxia

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Long intronic GAA repeats causing Friedreich ataxia impede transcription elongation

EMBO Molecular Medicine DOI 10.1002/emmm.201000064
Volume 2 Issue 4,;Pages 120-129, Published Online: 1 Apr 2010

Tanel Punga, Marc Bühler

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

Keywords: epigenetics • Friedreich ataxia (FRDA) • heterochromatic gene silencing • histone modification • triplet repeat expansion disorder (TRED)

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Cell and gene therapies: moving from research to clinic

Journal of Translational Medicine 2010, 8:31 (29 March 2010)

Stroncek DF, Puri RK
1Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland, USA
2Center for Biologics Evaluation and Research, Food and Drug Administration,
Bethesda, Maryland, USA

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North and South Indian Populations Share a Common Ancestral Origin of Friedreich's Ataxia but Vary in Age of GAA Repeat Expansion

Annals of Human Genetics, Early View (Articles online in advance of print)
Published Online: 31 Mar 2010

Inder Singh 1# , Mohammed Faruq 1,2# , Odity Mukherjee 3 , Sanjeev Jain 4 , Pramod Kumar Pal 4 , M. V. Padma Srivastav 1 , Madhuri Behari 1 , Achal K. Srivastava 1 and Mitali Mukerji 2*
1 Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India 2 Genomics and Molecular Medicine, Institute of Genomics and Integrative Biology, (IGIB) CSIR, Mall Road, New Delhi, India 3 National Centre for Biological Sciences, Bangalore, India 4 National Institute of Mental Health and Neuro Sciences, Bangalore, India

KEYWORDS: Age of mutation • CS2 • founder haplotype • FAD1 • FRDA • FR6 • FRDA India • GAA repeats • ITR3

La Ataxia de Friedreich, del pasado a la actualidad.- Friedreich Ataxia, from the past up to now

Holguín Ciencias. Año XV, No 4; Mes Diciembre 2009. ISSN 1027-2127

 1. Dra. Tania Cruz Mariño. Profesor Asistente. taniacmarin@infomed.sld.cu. Centro Municipal de Genética de Holguín. Calle Coliseo Esquina Mártires. Holguín. Cuba.
2. Lic. José Luis Guisao Martínez. Profesor Instructor. Agencia de Viajes Gaviotatours. Guardalavaca. Holguín.
3. Lic. Yanetza González Zaldivar. Investigador Agregado. yanetzag@ataxia.hlg.sld.cu

PALABRAS CLAVES: ATAXIA DE FRIEDREICH, ATAXIAS HEREDITARIAS, GEN FRDA

Computer Game Operated By Eye Movements Could Allow People With Severe Physical Disabilities To Become 'Gamers' For The First Time

The technology behind it could be adapted to create more sophisticated games and applications such as wheelchairs and computer cursors controlled by eye movements.

One of the major benefits of the new technology is that it is inexpensive, using off-the-shelf hardware and costing approximately £25 to make. 

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging

Particle and Fibre Toxicology 2010, 7:3doi:10.1186/1743-8977-7-3

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Sonu Bhaskar , Furong Tian , Tobias Stoeger , Wolfgang Kreyling , Jesus M de la Fuente , Valeria Grazu , Paul Borm , Giovani Estrada , Vasilis Ntziachristos  and Daniel Razansky 

Abstract (provisional)

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalised NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems. Nanocarriers are a cutting-edge technology poised to change the ways medicine is administered.

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Pathology and pathogenesis of sensory neuropathy in Friedreich’s ataxia

Acta Neuropathologica, DOI 10.1007/s00401-010-0675-0.
 Published online: 26 March 2010

Jennifer A. Morral¹, Ashley N. Davis¹, Jiang Qian², Benjamin B. Gelman³ and Arnulf H. Koeppen^{1, 2, 4} 

(1)	Research Service (151), VA Medical Center, 113 Holland Ave, Albany, NY 12208, USA

(2)	Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA

(3)	Department of Pathology and Laboratory Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA

(4)

Department of Neurology, Albany Medical College, Albany, NY 12208, USA

Keywords  Axons, Friedreich’s ataxia, Laminin,  Myelin sheath,  Neural crest ,  S100 protein,  Schwann cells, Sural nerve.

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