Signaling Pathways Regulating Neuronal Survival

描述（由申请人提供）：组蛋白去乙酰化酶（hdac）是最初根据其去乙酰化组蛋白导致转录抑制的能力而确定的蛋白质。hdac还使细胞核、细胞质和线粒体中的大量其他蛋白质去乙酰化，从而调节各种细胞事件。令人信服的证据表明，hdac调节神经元的存活和死亡。事实上，一些实验室已经证明，hdac的化学抑制剂在许多不同的实验性无脊椎动物和啮齿动物的神经退行性疾病模型中具有很强的保护作用。这项应用的重点是HDAC3，我们发现这种HDAC具有很强的神经毒性活性，代表了HDAC抑制剂的神经保护作用的可能目标。我们发现神经元对HDAC3毒性具有选择性敏感性，并且HDAC3诱导的神经元死亡需要GSK3¿的磷酸化，GSK3¿是一种与几种神经退行性疾病有关的激酶。目前的应用是在这些发现的基础上进一步研究HDAC3促进神经退行性变的机制。除了使用与疾病状态无关的神经元死亡范例外，我们还将研究HDAC3在亨廷顿病（HD）发病机制中的作用。我们已经观察到HDAC3与亨廷顿蛋白（Htt）相互作用，其突变导致HD。我们假设HDAC3在突变体- htt的神经毒性作用中起关键作用，突变体- htt刺激HDAC3的释放从而降低其神经毒性活性。根据最近获得的数据，我们提出HDAC3的神经毒性需要HDAC1的参与，HDAC1是与HDAC3相互作用的另一类HDAC。我们应用程序的具体目标是：(1)研究HDAC3对htt介导的神经元存活和突变-huntingtin诱导的神经元死亡的贡献；(2)研究HDAC1在HDAC3和突变- htt毒性中的作用；(3)确定HDAC3介导的神经毒性的下游靶点；(4)通过将R6/2和BACHD小鼠模型与我们刚刚培育的前脑特异性HDAC3条件敲除小鼠进行繁殖，研究HDAC3缺乏对HD小鼠神经病理学的影响。我们提出的研究将为神经元生存和死亡的基本机制以及这些机制与HD的关系提供新的见解。

DESCRIPTION (provided by applicant): 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.