Histone deacetylases (HDACs) are proteins originally identified on the basis of their ability to deacetylate histones resulting in transcriptionally repression. HDACs also deacetylate a large number of other proteins in the nucleus, cytoplasm and mitochondria thereby regulating diverse cellular events. Compelling evidence indicates that HDACs regulate the survival and death of neurons. Indeed, several laboratories have demonstrated that chemical inhibitors of HDACs are strongly protective in many different experimental invertebrate and rodent models of neurodegenerative disease. The focus of this application is on HDAC3, an HDAC that we discovered has strong neurotoxic activity and representing a likely target of HDAC inhibitors in their neuroprotective effect. We found that neurons are selectively sensitive to HDAC3 toxicity and that HDAC3-induced neuronal death requires its phosphorylation by GSK3 , a kinase implicated in several neurodegenerative disorders. The current application follows up on these findings to examine in more detail the mechanism by which HDAC3 promotes neurodegeneration. In addition to using paradigms of neuronal death unrelated to disease states, we will study the role of HDAC3 in Huntington disease (HD) pathogenesis. We have observed that HDAC3 interacts with huntingtin protein (Htt), mutation of which causes HD. We hypothesize that the HDAC3 plays a pivotal role in the neurotoxic effect of mutant-Htt and that mutant-Htt stimulates the release of HDAC3 thereby de-repressing its neurotoxic activity. Based on recently acquired data, we propose that HDAC3 neurotoxicity requires the participation of HDAC1, another Class I HDAC with which HDAC3 interacts. The specific goals of our application are: (1) To study the contribution of HDAC3 to Htt-mediated neuronal survival and to mutant-huntingtin-induced neuronal death, (2) To investigate the contribution of HDAC1 in HDAC3 and mutant-Htt toxicity, (3) To identify downstream targets of HDAC3- mediated neurotoxicity, and (4) To study the effect of HDAC3 deficiency on neuropathology in the R6/2 and BACHD mouse models of HD by breeding these mice to forebrain-specific HDAC3 conditional knockout mice that we have just generated. The studies we propose will shed new insight into the fundamental mechanisms regulating neuronal survival and death, as well as how these mechanisms relate to HD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040408-11
Application #
8616815
Study Section
Special Emphasis Panel (ZRG1-MDCN-E (03))
Program Officer
Sutherland, Margaret L
Project Start
2000-08-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
11
Fiscal Year
2014
Total Cost
$331,341
Indirect Cost
$114,778
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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