Aaron G Filler , Garth T Whiteside , Mark Bacon , Martyn Frederickson , Franklyn A Howe , Miri D Rabinowitz , Alan J Sokoloff , Terrence W Deacon , Chris Abell , Raj Munglani , John R Griffiths , B ANTHONY Bell and Andrew ML Lever
BMC Neuroscience 2010, 11:8doi:10.1186/1471-2202-11-8, Published: 20 January 2010
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Background
Targeted delivery of pharmaceutical agents into selected populations of CNS neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.
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Wednesday, January 20, 2010
Neurons Developed from Stem Cells Successfully Wired With Other Brain Regions in Animals
ScienceDaily (Jan. 19, 2010) — Transplanted neurons grown from embryonic stem cells can fully integrate into the brains of young animals, according to new research in the Jan. 20 issue of The Journal of Neuroscience.
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Sunday, January 17, 2010
Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies
Russell H. Swerdlow
Departments of Neurology and Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, MO, Kansas 66160, USA
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Departments of Neurology and Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, MO, Kansas 66160, USA
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Abstract: Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed.
Keywords: mitochondria; mitochondrial biogenesis; mitochondriopathies; neurodegenerative diseases; oxidative stress
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Friday, January 15, 2010
Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology
Citation: Haugen AC, Di Prospero NA, Parker JS, Fannin RD, Chou J, et al. (2010) Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology. PLoS Genet 6(1): e1000812. doi:10.1371/journal.pgen.1000812
Editor: Christopher E. Pearson, The Hospital for Sick Children and University of Toronto, Canada
Received: May 5, 2009; Accepted: December 10, 2009; Published: January 15, 2010
OPEN ACCESS This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Abstract
The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.
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Editor: Christopher E. Pearson, The Hospital for Sick Children and University of Toronto, Canada
Received: May 5, 2009; Accepted: December 10, 2009; Published: January 15, 2010
OPEN ACCESS This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Abstract
The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.
FULL TEXT
Excess DNA damage found in cells of patients with Friedreich's ataxia. Biomarkers, new treatments possible for Friedreich's ataxia
Genetic Engineering & Biotechnology News, PITTSBURGH, Jan. 14
Thursday, January 14, 2010
Autosomal recessive ataxias: 20 types, and counting
Embiruçu EK, Martyn ML, Schlesinger D, Kok F.
Outpatient Neurogenetics Clinic, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, SP, Brazil.
Keywords: Friedreich ataxia, autosomal recessive ataxias, neurogenetics, clinical and pathophysiological aspects, diagnosis.
Outpatient Neurogenetics Clinic, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, SP, Brazil.
Keywords: Friedreich ataxia, autosomal recessive ataxias, neurogenetics, clinical and pathophysiological aspects, diagnosis.
Tuesday, January 12, 2010
Treatment of mitochondrial electron transport chain disorders: A review of clinical trials over the past decade.
Mol Genet Metab. 2009 Nov 26. [Epub ahead of print]
Center for Inherited Disorders of Metabolism, University Hospitals Case Medical Center, Rainbow Babies and Childrens Hospital, Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-6004, USA.
Keywords: mitochondrial electron transport chain disorders, controlled clinical trials, dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, neuropathy, Friedreich ataxia, cardiomyopathy, neurological protection.
Keywords: mitochondrial electron transport chain disorders, controlled clinical trials, dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, neuropathy, Friedreich ataxia, cardiomyopathy, neurological protection.
Monday, January 11, 2010
Penwest Announces Initiation of Phase IIa Clinical Trial of A0001 in Patients With Friedreich's Ataxia
PATTERSON, N.Y., Jan. 11, 2010 (GLOBE NEWSWIRE)
Sunday, January 10, 2010
Measuring the rate of progression in Friedreich ataxia: Implications for clinical trial design
Movement Disorders, Early View (Articles online in advance of print)
Published Online: 8,Jan,2010
Lisa S. Friedman, BS 1 2 3, Jennifer M. Farmer, MS 1 2 3, Susan Perlman, MD 4, George Wilmot, MD, PhD 5, Christopher M. Gomez, MD PhD 6 7, Khalaf O. Bushara, MD 6, Katherine D. Mathews, MD 8, S. H. Subramony, MD 9 10, Tetsuo Ashizawa, MD 9 11, Laura J. Balcer, MD, MSCE 1, Robert B. Wilson, MD, PhD 12, David R. Lynch 1 2 3 *1Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
2Department of Pediatrics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
3Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
4Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
5Department of Neurology, Emory University, Atlanta, Georgia, USA
6Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA
7Department of Neurology, University of Chicago, Chicago, Illinois, USA
8Departments of Neurology and Pediatrics, University of Iowa, Iowa City, Iowa, USA
9Department of Neurology, University of Texas Medical Branch, Galveston, Texas, USA
10Department of Neurology, University of Mississippi, Jackson, Mississippi, USA
11Department of Neurology, University of Florida, Gainesville, Florida, USA
12Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Keywords: Friedreich ataxia, natural history study, clinical neurology examination, mitochondrial disorder, trinucleotide repeat disease
Published Online: 8,Jan,2010
Lisa S. Friedman, BS 1 2 3, Jennifer M. Farmer, MS 1 2 3, Susan Perlman, MD 4, George Wilmot, MD, PhD 5, Christopher M. Gomez, MD PhD 6 7, Khalaf O. Bushara, MD 6, Katherine D. Mathews, MD 8, S. H. Subramony, MD 9 10, Tetsuo Ashizawa, MD 9 11, Laura J. Balcer, MD, MSCE 1, Robert B. Wilson, MD, PhD 12, David R. Lynch 1 2 3 *1Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
2Department of Pediatrics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
3Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
4Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
5Department of Neurology, Emory University, Atlanta, Georgia, USA
6Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA
7Department of Neurology, University of Chicago, Chicago, Illinois, USA
8Departments of Neurology and Pediatrics, University of Iowa, Iowa City, Iowa, USA
9Department of Neurology, University of Texas Medical Branch, Galveston, Texas, USA
10Department of Neurology, University of Mississippi, Jackson, Mississippi, USA
11Department of Neurology, University of Florida, Gainesville, Florida, USA
12Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Keywords: Friedreich ataxia, natural history study, clinical neurology examination, mitochondrial disorder, trinucleotide repeat disease
Friday, January 8, 2010
Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin.
Hum Mol Genet. 2010 Jan 6.
Condò I, Malisan F, Guccini I, Serio D, Rufini A, Testi R.
Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Rome.
Keywords: , frataxin, Friedreich's Ataxia (FRDA), progressive gait instability, cardiomyopathy, high incidence of diabetes, iron-binding protein, iron-sulfur clusters (ISC), iron-chaperone, extramitochondrial pool of mature frataxin, cytosolic aconitase/IRP1, enzymatic and a RNA-binding function, IRP1 activation.
Condò I, Malisan F, Guccini I, Serio D, Rufini A, Testi R.
Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Rome.
Keywords: , frataxin, Friedreich's Ataxia (FRDA), progressive gait instability, cardiomyopathy, high incidence of diabetes, iron-binding protein, iron-sulfur clusters (ISC), iron-chaperone, extramitochondrial pool of mature frataxin, cytosolic aconitase/IRP1, enzymatic and a RNA-binding function, IRP1 activation.
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