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

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD038466-09S1
Application #
8097125
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Vitkovic, Ljubisa
Project Start
2010-08-01
Project End
2011-06-28
Budget Start
2010-08-01
Budget End
2011-06-28
Support Year
9
Fiscal Year
2010
Total Cost
$50,654
Indirect Cost
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Helguera, Pablo; Seiglie, Jaqueline; Rodriguez, Jose et al. (2013) Adaptive downregulation of mitochondrial function in down syndrome. Cell Metab 17:132-40
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Garcia, Octavio; Torres, Maria; Helguera, Pablo et al. (2010) A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome. PLoS One 5:e14200
Deshpande, Atul; Kawai, Hideki; Metherate, Raju et al. (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004-15
Deshpande, Atul; Win, Khin May; Busciglio, Jorge (2008) Tau isoform expression and regulation in human cortical neurons. FASEB J 22:2357-67

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