The molecular mechanisms that regulate neuronal cell death during human neurodegenerative diseases remain unclear. One intracellular pathway that may function in regulating neuronal cell death includes the activation of cell cycle transcription factors that alter gene expression and chromatin structure. Key protein components of the cell cycle regulated death of neurons include p53, E2F1 and the retinoblastoma protein (pRb). These proteins participate in cell death induced by DNA damage, oxidative injury and the Abeta peptide. We have identified novel functional interactions between the FAC1 and ZF87/MAZ transcription factors with pRb_2F1 and propose that interactions between p53, pRb, E2F1, FAC1, and ZF87/MAZ pathways play a pivotal role to regulate cell survival or death during human neurodegenerative diseases. We hypothesize that altered expression of downstream genes and chromatin structure leads to neuronal cell death in neurodegenerative diseases. Our first Specific Aim will directly test the function of these transcription factors in two in vitro models of neurodegeneration.
The second Aim will test the hypothesis that these transcriptional regulators regulate neurodegeneration in an animal model of neurologic disease. Specific drugs that affect cell cycle proteins will be examined for their ability to slow disease onset and increase survival in this animal model. The last Aim will examine the distribution and function of transcription factors during Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and to determine their presence in degenerating neurons. The combination of in vitro and in vivo studies will demonstrate the physiologic relevancy for our proposed model. Our proposed studies will greatly increase our understanding of the role that cell cycle transcription factors play in regulating neuronal death during human neurodegenerative diseases and lead to novel therapeutic strategies to enhance neuronal survival during brain injury and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042724-02
Application #
6829662
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Murphy, Diane
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$260,611
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ranganathan, Srikanth; Bowser, Robert (2010) p53 and Cell Cycle Proteins Participate in Spinal Motor Neuron Cell Death in ALS. Open Pathol J 4:11-22
Caltagarone, John; Hamilton, Ronald L; Murdoch, Geoffrey et al. (2010) Paxillin and hydrogen peroxide-inducible clone 5 expression and distribution in control and Alzheimer disease hippocampi. J Neuropathol Exp Neurol 69:356-71
Jing, Zheng; Caltagarone, John; Bowser, Robert (2009) Altered subcellular distribution of c-Abl in Alzheimer's disease. J Alzheimers Dis 17:409-22
Bowser, Robert; Lacomis, David (2009) Applying proteomics to the diagnosis and treatment of ALS and related diseases. Muscle Nerve 40:753-62
Caltagarone, John; Jing, Zheng; Bowser, Robert (2007) Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease. Biochim Biophys Acta 1772:438-45
Yu, Xiaoyi; Caltagarone, John; Smith, Mark A et al. (2005) DNA damage induces cdk2 protein levels and histone H2B phosphorylation in SH-SY5Y neuroblastoma cells. J Alzheimers Dis 8:7-21