Abstract

Down's syndrome (DS) or trisomy 21 is the most frequent genetic cause of mental retardation. It occurs in about 1 in 800 to 1 in 1000 live births. Mental retardation and development of Alzheimer's disease (AD) by middle age are hallmarks of DS neuropathology. Previous studies demonstrated that DS neurons in culture exhibit elevated intracellular free radicals and lipid peroxidation leading to increased neuronal death. This increase in oxidative stress and neurodegeneration may contribute to mental retardation and the development of AD in DS patient. The goal of our research is to characterize the molecular mechanisms involved in neuronal oxidative stress and degeneration in DS. This project will study the role of Ets-2 and Cu/Zn superoxide dismutase (SOD-1) over- expression in DS neurodegeneration. The following hypotheses will be tested: 1. Over-expression of the transcription factor Ets-2 in DS neurons compromises neuronal viability by altering the expression of genes that control neuronal survival and death. More specifically, the possibility that Ets-2 down-regulates Bcl-2 and up-regulates Bax and p53 protein levels will be tested. 2. Increased activity of Cu/Zn superoxide dismutase (SOD- 1) may contribute to oxidative stress and DS neuronal degeneration. The research will focus on: 1) the functional analysis of Ets-2 and SOD-1 in DS and Ets-2 transgenic neurons in culture; and 2) the association of Ets- 2 and SOD-1 with neurodegenerative changes in the brains of DS and AD patients and Ets-2 transgenic mice.
The specific aims are: 1: to determine the role of Ets-2 over-expression in DS neuronal degeneration in culture and in the brains of DS and AD patients. 2: To characterize the role of Ets-2 during normal neuronal development. 3: To determine the role of SOD-1 in DS neuronal degeneration. These experiments will provide valuable information towards understanding the molecular basis of neuronal dysfunction and death in DS and AD. In addition, the results of this investigation may identify new molecular targets for the design of neuroprotective therapies for the treatment of mental retardation and the prevention of AD in DS patients.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038466-02
Application #
6363452
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
2000-03-01
Project End
2004-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$135,606
Indirect Cost

  Institution

Name
University of Connecticut
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030

  Publications

Iulita, M Florencia; Do Carmo, Sonia; Ower, Alison K et al. (2014) Nerve growth factor metabolic dysfunction in Down's syndrome brains. Brain 137:860-72
Sosa, Lucas J; Postma, Nienke L; Estrada-Bernal, Adriana et al. (2014) Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome. FASEB J 28:195-205
Helguera, Pablo; Seiglie, Jaqueline; Rodriguez, Jose et al. (2013) Adaptive downregulation of mitochondrial function in down syndrome. Cell Metab 17:132-40
Yeo, Michele; Berglund, Ken; Hanna, Michael et al. (2013) Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci U S A 110:4315-20
Coskun, Pinar E; Busciglio, Jorge (2012) Oxidative Stress and Mitochondrial Dysfunction in Down's Syndrome: Relevance to Aging and Dementia. Curr Gerontol Geriatr Res 2012:383170
Tiano, Luca; Busciglio, Jorge (2011) Mitochondrial dysfunction and Down's syndrome: is there a role for coenzyme Q(10) ? Biofactors 37:386-92
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
Rahman, Ardeshir S; Parvinjah, Shaudee; Hanna, Michael A et al. (2010) Cryopreservation of cortical tissue blocks for the generation of highly enriched neuronal cultures. J Vis Exp :
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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