Validation of IKKbeta as a therapeutic target for HD

描述（由申请人提供）：亨廷顿病（HD）是一种常遗传的神经退行性疾病，由亨廷顿蛋白（Htt）外显子1 CAG重复扩增引起。酶裂解突变的Htt蛋白导致产生神经毒性的淀粉样蛋白片段，是HD发病的最早事件之一。然而，调控Htt切割的环境因素和信号通路尚不清楚。HD是一种年龄依赖性疾病，与年龄相关的因素，如DNA损伤的积累和神经炎症可能影响其进展。IkB激酶(IKK)/NF-kB信号通路被这些环境因素激活，并与HD的发病机制有关。IKK吗?对DNA损伤有反应并介导炎症反应。我们的研究结果表明，症状前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？大脑其他区域的活动，包括皮层。抑制IKK？在HD的脑切片培养模型中降低Htt淀粉样蛋白片段的神经毒性。我们还发现IKK？DNA损伤诱导的激活促进了有丝分裂后人类神经元中caspase依赖性WT和突变体Htt的切割。遗传和化学抑制IKK？防止半胱天冬酶激活和Htt切割，同时增加神经元对DNA损伤的恢复能力。最近的研究暗示IKK？Htt的n端（Ser13和Ser16）的磷酸化。这些残基的模拟磷修饰可改善HD小鼠的疾病。我们实验室和其他研究人员的初步研究表明，IKK？在神经元模型中，抑制可促进Htt的磷酸化。因此,IKK吗?是HD发病机制的关键调节因子，其抑制可能对HD有保护作用。此外，解除对IKK？可能导致神经炎症，在患者出现运动症状前几年就会发生。我们建议调查IKK？在几种动物模型中HD的发病机制我们将删除IKK？在HD小鼠的大脑中，并检查IKK？防止Htt切割，神经炎症，从而改善病理。此外，我们计划测试IKK？作为HD的潜在新疗法

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.