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. 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
  2. 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
  3. ncbi 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
  4. ncbi 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

Scientific Experts

  • JORGE A BUSCIGLIO
  • Atul Deshpande
  • Pablo Helguera
  • Raju Metherate
  • Charles G Glabe
  • Hideki Kawai
  • Khin May Win
  • Elizabeth Head
  • Ernst Wolvetang
  • Gustavo Pigino
  • Alejandra Pelsman

Detail Information

Publications4

  1. 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
    ....
  2. 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
    ....
  3. ncbi 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...
  4. ncbi 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...