The overall objective of our proposal is to understand the role of histone deacetylases (HDACs) in the regulation of neuronal survival and death. We plan to continue our research on histone deacetylase-related protein (HDRP), which we identified as a protein with strong neuroprotective activity. We found that the neuroprotective effect of HDRP is dependent on deacetylase activity which is acquired through interaction with HDAC1. More recently we discovered that HDAC3 has strong neurotoxic activity, which is also dependent on HDAC1. And like HDRP, HDAC3 interacts with HDAC1. In the first part of our proposal we will study the relationship between HDAC1, HDRP and HDAC3 in the regulation of neuronal survival. The hypothesis underlying this part of our proposal is that HDAC1 is a molecular switch that promotes both neuroprotection and neurotoxicity depending on whether it interacts with HDRP or HDAC3, respectively. A second part of our proposal focuses on HDAC3 and looks into its involvement in Huntington Disease (HD) pathogenesis. Our hypothesis is that the HDAC3 plays a pivotal role in the neurotoxic effect of mutant huntingtin (Htt) but that under normal circumstances this neurotoxicity is prevented through its sequestration by wild-type Htt. We also propose that IGF-1-Akt signaling, generally believed to protect against mutant Htt toxicity by the phosphorylating it, actually acts by inhibiting the GSK3 -mediated phosphorylation of HDAC3. The specific goals of our proposal are:
Aim 1 : To determine the significance of interactions between HDAC1, HDRP, and HDAC3 to the regulation of neuronal death.
Aim 2 : To examine the relationship between GSK3 phosphorylation and HDAC1-HDAC3 interaction.
Aim 3 : To identify downstream targets of HDAC3-mediated neurotoxicity.
Aim 4 : To study the role of HDAC3 in mutant Htt-induced neuronal death in vitro.
Aim 5 : To study the effect of HDAC3 deficiency on neuropathology in the R6/2 mouse model of HD. We believe our studies will shed new insight into the fundamental mechanisms regulating neuronal survival and death, as well as how these mechanisms relate to neurodegenerative brain disorders.

Public Health Relevance

Histone deacetylases (HDACs) are a family of proteins that play important roles in the regulation of neuronal survival and death. We propose to study the inter-relationship between three HDAC proteins, HDRP, HDAC1 and HDAC3, in the regulation of neuronal survival. We will also test the hypothesis that one of these HDACs, HDAC3, plays a key role in promoting neuronal death Huntington's disease. We believe our studies will shed new insight into the fundamental mechanisms regulating neuronal survival and death, as well as how these mechanisms relate to neurodegenerative brain disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-E (03))
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Sutherland, Margaret L
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Southern Methodist University
Schools of Arts and Sciences
United States
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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
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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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