Validation of IKKbeta as a therapeutic target for HD

描述(申请人提供)：亨廷顿病(HD)是一种常染色体遗传性神经退行性疾病，由亨廷顿蛋白(Htt)外显子1中CAG重复序列的扩大引起。突变的Htt蛋白的酶切导致神经毒性的淀粉样蛋白片段的产生，是HD发病机制中最早的事件之一。然而，调控Htt裂解的环境线索和信号通路却知之甚少。HD是一种年龄依赖性疾病，与年龄相关的因素，如DNA损伤和神经炎症的积累，可能会影响其进展。这些环境因素激活了IKB激酶(IKK)/NF-kB信号通路，参与了HD的发病机制。伊克？对DNA损伤有反应，并介导炎症反应。我们的结果表明，有症状的HD小鼠的IKK？活动局限于纹状体，而有症状的HD小鼠也表现出IKK？包括大脑皮质在内的其他大脑区域的活动。抑制IKK？在HD脑片培养模型中降低Htt淀粉样变性片段的神经毒性。我们也找到了那本书吗？DNA损伤诱导的激活促进了有丝分裂后人类神经元中依赖于caspase的Wt和突变的Htt的切割。IKK的遗传和化学抑制？防止caspase激活和Htt裂解，同时增加神经元对DNA损伤的弹性。最近的研究表明ikk？在Htt的N末端(Ser13和Ser16)的磷酸化。这些残基的磷酸模拟修饰可以改善HD小鼠的疾病。我们实验室和其他调查人员的初步研究表明，ikk？抑制促进神经元模型中Htt的磷酸化。这么说来，好吗？是HD发病的关键调节因子，其抑制可能对HD具有保护作用。此外，放松管制的IKK？可能是神经炎的原因，这种炎症在患者出现运动症状之前几年就会发生。我们建议研究ikk？几种动物模型在HD发病机制中的作用。我们将删除ikk吗？并在HD小鼠的大脑中检查是否缺乏ikk？防止Htt卵裂，神经炎症，从而改善病理。此外，我们计划测试IKK？小分子抑制剂的疗效。作为治疗HD的潜在的新疗法。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomally inherited neurodegenerative disorder that is caused by expansion of CAG repeats in exon-1 of huntingtin (Htt). Enzymatic cleavage of mutant Htt protein leads to the generation of neurotoxic, amyloidogenic fragments and is one of the earliest events in HD pathogenesis. The environmental cues and the signaling pathways that regulate Htt cleavage are poorly understood, however. HD is an age-dependent disorder and age-related factors such as the accumulation of DNA damage and neuroinflammation are likely to influence its progression. The IkB kinase (IKK)/NF-kB signaling pathway is activated by these environmental factors and is implicated in the pathogenesis of HD. IKK? is responsive to DNA damage and mediates inflammatory responses. Our results demonstrate that pre- symptomatic HD mice have elevated IKK? activity localized to the striatum, while symptomatic HD mice also exhibit elevated IKK? activity in other brain regions including cortex. Inhibition of IKK? reduces the neurotoxicity of amyloidogenic fragments of Htt in a brain slice culture model of HD. We also find that IKK? activation induced by DNA damage promotes caspase-dependent WT and mutant Htt cleavage in post-mitotic human neurons. Genetic and chemical inhibition of IKK? prevents caspase activation and Htt cleavage, while increasing neuronal resiliency to DNA damage. Recent studies implicate IKK? in the phosphorylation of N-terminus (Ser13 and Ser16) of Htt. Phospho- mimetic modification of these residues ameliorates disease in HD mice. Preliminary studies from our laboratory and other investigators indicate that IKK? inhibition promotes the phosphorylation of Htt in neuronal models. Thus, IKK? is a key regulator of HD pathogenesis and its inhibition may be protective in HD. Moreover, deregulated IKK? is likely responsible for neuroinflammation, which occurs years before the onset of motor symptoms in patients. We propose to investigate the role of IKK? in HD pathogenesis in several animal models. We will delete IKK? in the brains of HD mice and examine whether the lack of IKK? prevents Htt cleavage, neuroinflammation and thereby ameliorates pathology. Furthermore, we plan to test the efficacy of small molecule inhibitors of IKK? as potentially novel therapeutics for HD.