A common feature of most neurological diseases is the premature and aberrant degeneration of neurons. A variety of molecules involved in the promotion or inhibition of neuronal survival have been identified. This proposal focuses on histone deacetylases (HDACs),a family of enzymes that have become the subject of intense investigation recently. Accumulating evidence suggests that in addition to their involvement in a variety of different biological processes, HDACs regulate neuronal survival. The goal of this proposal is to better understand the role of HDACs in the regulation of neuronal survival. The proposal is based on our recent finding that HDAC-relatedprotein (HDRP), an HDAC that is highly expressed in the brain, protects cultured cerebellar and cortical neurons from apoptosis. We also found that c-jun, a protein that is necessary for neurodegeneration in a variety of in vivo and in vitro paradigms is inhibited by HDRP. The inhibition of c-jun is mediated by the direct interaction of HDRPwith c-jun N-terminal kinase (JNK), the enzyme that activates c-jun through its phosphorylation. The overall objective of the proposal is to better undertand the mechanism underlying HDRP-mediated neuroprotection in the hope of developing novel strategies to treat neurodegenerative pathologies. The hypothesis underlying our proposal is that HDRP acts through interaction with JNK, as well as other signaling proteins. Long-term HDRP- deficiency will render the brain vulnerable to damage while overexpression of HDRP in the brain will protect it from neurotoxic insults. One of our specific goals is identify HDRP-interacting proteins in the brain by yeast-two hybrid screening. The role of these interacting proteins in HDRP-mediated neuroprotection will then be studied. Another goal will be to examine how the interaction between HDRP and JNK inhibits c-jun activation using a variety of biochemical and molecular biological approaches. A third goal will be to to examine whether the brains of HDAC-deficient mice possess any abnormalities. Focus will also be placed on characterizing the nature of lesions within the brains of older HDAC-deficient mice. The fourth goal and final goal of our proposal is to examine whether transgenic mice overexpressing HDRP in the brain are more resistant to neuronal loss in an in vivo experimental model of neurodegenerative disease.

Public Health Relevance

Neurological diseases disrupt the quality of life for patients and cost society billions of dollars annually. While symptomatic treatments are available for many neurological diseases, a cure is not presently available. It is our hope that the results from the studies we propose will shed insight into how HDRP prevents neuronal loss and thus provide novel targets for the development of strategies to treat neurodegenerative pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040408-09
Application #
8029535
Study Section
Special Emphasis Panel (ZRG1-NOMD-A (01))
Program Officer
Sieber, Beth-Anne
Project Start
2000-08-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2011
Total Cost
$365,050
Indirect Cost
Name
University of Texas-Dallas
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800188161
City
Richardson
State
TX
Country
United States
Zip Code
75080
Pfister, Jason A; D'Mello, Santosh R (2016) Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status. J Biol Chem 291:20787-97
Rawat, Varun; Goux, Warren; Piechaczyk, Marc et al. (2016) c-Fos Protects Neurons Through a Noncanonical Mechanism Involving HDAC3 Interaction: Identification of a 21-Amino Acid Fragment with Neuroprotective Activity. Mol Neurobiol 53:1165-80
Garcia-Oscos, Francisco; Peña, David; Housini, Mohammad et al. (2015) Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex. Brain Behav Immun 43:149-58
Sharma, Dharmendra; Kim, Min Soo; D'Mello, Santosh R (2015) Transcriptome profiling of expression changes during neuronal death by RNA-Seq. Exp Biol Med (Maywood) 240:242-51
Pfister, Jason A; D'Mello, Santosh R (2015) Insights into the regulation of neuronal viability by nucleophosmin/B23. Exp Biol Med (Maywood) 240:774-86
Verma, Pragya; Pfister, Jason A; Mallick, Sathi et al. (2014) HSF1 protects neurons through a novel trimerization- and HSP-independent mechanism. J Neurosci 34:1599-612
Mallick, Sathi; D'Mello, Santosh R (2014) JAZ (Znf346), a SIRT1-interacting protein, protects neurons by stimulating p21 (WAF/CIP1) protein expression. J Biol Chem 289:35409-20
Norwood, Jordan; Franklin, Jade M; Sharma, Dharmendra et al. (2014) Histone deacetylase 3 is necessary for proper brain development. J Biol Chem 289:34569-82
Rangasamy, Sampathkumar; D'Mello, Santosh R; Narayanan, Vinodh (2013) Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics 10:742-56
Price, Valerie; Wang, Lulu; D'Mello, Santosh R (2013) Conditional deletion of histone deacetylase-4 in the central nervous system has no major effect on brain architecture or neuronal viability. J Neurosci Res 91:407-15

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