Mitochondrial Dysfunction in Down's Syndrome

Summary

Principal Investigator: JORGE A BUSCIGLIO
Affiliation: University of California
Country: USA
Abstract: Down's syndrome (DS) or trisomy 21 is the most common autosomal aneuploidy that survives birth and it is the single most frequent genetic cause of mental retardation. The number of DS patients in the.United States is estimated to be more than 350,000. Abnormal mitochondria! function cause selective neuronal degeneration and is associated with a variety of disorders including DS. During this grant period, we have obtained results indicating that: 1) mitochondrial dysfunction exist in DS neurons and astrocytes, which leads to aberrant amyloid (i precursor protein (APR) metabolism and intracellular amyloid IS (Afi) accumulation;2) there are mitochondrial structural and functional alterations in DS neurons, astrocytes, fibroblast and lymphoblastoid cells;and 3) the mitochondrial localization of Mfn1 and Drp1, which are proteins that participate in the regulation of mitochondrial morphology and activity is altered in DS brains and DS cultured cells. We hypothesize that mitochondrial dysfunction in DS may lead to a persistent deficit in energy production and chronic oxidative stress, two critical factors in the development of DS neuropathology and the development of AD in DS subjects. To further understand the role of mitochondrial dysfunction in DS, we propose the following specific aims: 1) to characterize the structural and functional alterations in DS mitochondria;2) to characterize the molecular determinants of mitochondrial dysfunction in DS;and 3) to analyze mitochondrial alterations in limphoblastoid cells of DS patients, and to determine the relevance of mitochondrial dysfunction as a predictor of AD pathology in DS. Normal and DS brain tissue samples, normal and DS cortical neurons, astrocytes and fibroblast cultures will be utilized to characterize mitochondrial structure and function and to study the molecular components involved in DS mitochondrial dysfunction. Fibroblast and limphoblastoid cells derived from normal and DS subjects will be utilized to analyze the existence of mitochondrial dysfunction in peripheral tissues, and limphoblastoid cells will be used to evaluate the relation between mitochondrial dysfunction and the presence of AD in DS subjects. These experiments will provide novel information on mitochondrial structure and function in DS that may be critical to understand the role of energy impairment in neurodegenerativedisorders, and to design therapies directed to prevent neuronal dysfunction and the progression of AD neuropathology in DS patients
Funding Period: 2000-03-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Nerve growth factor metabolic dysfunction in Down's syndrome brains
    M Florencia Iulita
    1 Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal, H3G1Y6, Canada
    Brain 137:860-72. 2014
  2. pmc Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome
    Lucas J Sosa
    3Department of Pediatrics, University of Colorado, Mailbox 8313, 12800 E 19th Ave, Aurora, CO 80045, USA
    FASEB J 28:195-205. 2014
  3. pmc Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter
    Michele Yeo
    Department of Medicine Neurology, Duke University, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 110:4315-20. 2013
  4. pmc Adaptive downregulation of mitochondrial function in down syndrome
    Pablo Helguera
    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA
    Cell Metab 17:132-40. 2013
  5. doi Mitochondrial dysfunction and Down's syndrome: is there a role for coenzyme Q(10) ?
    Luca Tiano
    Department of Biochemistry, Biology and Genetics, Polytechnic University of the Marche, Ancona, Italy
    Biofactors 37:386-92. 2011
  6. pmc A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome
    Octavio Garcia
    Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California, United States of America
    PLoS ONE 5:e14200. 2010
  7. doi A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses
    Atul Deshpande
    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA
    J Neurosci 29:4004-15. 2009
  8. doi Tau isoform expression and regulation in human cortical neurons
    Atul Deshpande
    Department of Neurobiology and Behavior, University of California, Irvine, CA 92697 4550, USA
    FASEB J 22:2357-67. 2008
  9. ncbi NAP and ADNF-9 protect normal and Down's syndrome cortical neurons from oxidative damage and apoptosis
    Jorge Busciglio
    Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
    Curr Pharm Des 13:1091-8. 2007
  10. ncbi ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons
    Pablo Helguera
    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697 4550, USA
    J Neurosci 25:2295-303. 2005

Scientific Experts

  • JORGE A BUSCIGLIO
  • Luca Tiano
  • Pablo Helguera
  • Atul Deshpande
  • Michael Hanna
  • M Florencia Iulita
  • Lucas J Sosa
  • Michele Yeo
  • Octavio Garcia
  • Lisi Flores Aguilar
  • Karl H Pfenninger
  • Thomas Wisniewski
  • Mona Buhusi
  • A Claudio Cuello
  • Alison K Ower
  • Adriana Estrada-Bernal
  • Nienke L Postma
  • Ashley M Fortress
  • M Hanna
  • R Guo
  • Sonia Do Carmo
  • Ann Charlotte Granholm
  • Ken Berglund
  • MarĂ­a D Torres
  • Jose Rodriguez
  • Lutz Birnbaumer
  • Joel Abramowitz
  • Jaqueline Seiglie
  • Jaya Kittur
  • Yuan Gao
  • Gustavo Helguera
  • Junjie U Guo
  • WOLFGANG B LIEDTKE
  • Maria Torres
  • Pinar Coskun
  • Charles G Glabe
  • Hideki Kawai
  • Raju Metherate
  • Khin May Win
  • Ernst Wolvetang
  • Elizabeth Head
  • Gustavo Pigino
  • Alejandra Pelsman

Detail Information

Publications11

  1. pmc Nerve growth factor metabolic dysfunction in Down's syndrome brains
    M Florencia Iulita
    1 Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal, H3G1Y6, Canada
    Brain 137:860-72. 2014
    ..Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome. ..
  2. pmc Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome
    Lucas J Sosa
    3Department of Pediatrics, University of Colorado, Mailbox 8313, 12800 E 19th Ave, Aurora, CO 80045, USA
    FASEB J 28:195-205. 2014
    ..The results suggest that APP overexpression may perturb axonal pathfinding and circuit formation in developing DS brain...
  3. pmc Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter
    Michele Yeo
    Department of Medicine Neurology, Duke University, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 110:4315-20. 2013
    ..Beyond increase in basic understanding, our findings have relevance for identifying unique neurodevelopmental toxicity mechanisms of BPA, which could possibly play a role in pathogenesis of human neurodevelopmental disorders...
  4. pmc Adaptive downregulation of mitochondrial function in down syndrome
    Pablo Helguera
    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA
    Cell Metab 17:132-40. 2013
    ....
  5. doi Mitochondrial dysfunction and Down's syndrome: is there a role for coenzyme Q(10) ?
    Luca Tiano
    Department of Biochemistry, Biology and Genetics, Polytechnic University of the Marche, Ancona, Italy
    Biofactors 37:386-92. 2011
    ..Results suggest that the effect of CoQ(10) treatment in DS not only reflects antioxidant efficacy, but likely modulates DNA repair mechanisms...
  6. pmc A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome
    Octavio Garcia
    Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California, United States of America
    PLoS ONE 5:e14200. 2010
    ..In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology...
  7. doi A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses
    Atul Deshpande
    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA
    J Neurosci 29:4004-15. 2009
    ..In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss...
  8. doi Tau isoform expression and regulation in human cortical neurons
    Atul Deshpande
    Department of Neurobiology and Behavior, University of California, Irvine, CA 92697 4550, USA
    FASEB J 22:2357-67. 2008
    ..Thus, experimentally induced changes in tau activity and function in HCNs recapitulate critical features of tauopathies that may lead to neuronal dysfunction and degeneration in the human brain...
  9. ncbi NAP and ADNF-9 protect normal and Down's syndrome cortical neurons from oxidative damage and apoptosis
    Jorge Busciglio
    Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
    Curr Pharm Des 13:1091-8. 2007
    ....
  10. ncbi ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons
    Pablo Helguera
    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697 4550, USA
    J Neurosci 25:2295-303. 2005
    ....