FoxP1 as a therapeutic target for Huntington's disease

FoxP1作为亨廷顿病的治疗靶点

• 批准号: 9513211
• 负责人: Santosh R D'Mello
• 金额: $ 37.52万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513211
• 关键词: Adult; Behavioral; Brain; CAG repeat; CDKN1A gene; Candidate Disease Gene; Cell Culture Techniques; Cessation of life; Corpus striatum structure; Development; Dimerization; Disease; Disease Progression; Disease model; Down-Regulation; Drosophila genus; Ectopic Expression; Event; Exons; FOXP1 gene; FOXP2 gene; Family; Genes; HDAC3 gene; Human; Huntington Disease; Huntington gene; Knockout Mice; Mediating; Medical Economics; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Patients; Play; Protein Family; Protein Isoforms; Proteins; Regulation; Role; Severity of illness; Signal Transduction; Social Problems; Testing; Toxic effect; Transgenes; Transgenic Mice; Validation; differential expression; dimer; effective therapy; fly; gene repression; hippocampal pyramidal neuron; in vivo; in vivo Model; insight; knock-down; member; mouse model; mutant; neuron loss; neuronal survival; neuroprotection; neurotoxicity; novel therapeutic intervention; novel therapeutics; polyglutamine; protective effect; public health relevance; selective expression; therapeutic target; tissue culture; transcription factor; transcriptome sequencing; treatment strategy

SUMMARY Huntington disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat in the first exon of the huntingtin gene resulting in a mutant protein with a poly-glutamine expansion. Although mutant huntingtin (mut-Htt) is expressed ubiquitously in the brain, neurodegeneration occurs selectively in the striatum and, to a lesser degree, the cortex. We propose that a key factor in the region-specific vulnerability in HD is a reduction in the expression of FoxP1, a neuroprotective protein that is expressed selectively in medium spiny neurons of the striatum and to a relatively lower level in pyramidal neurons of the cortex. Consistent with our hypothesis, FoxP1 expression is reduced in the striatum of HD patients and HD mouse models. Elevating FoxP1 expression in cultured neurons protects them from mut-Htt toxicity, while knocking down its expression induces death in otherwise healthy neurons. The overall objective of the proposal is to understand the mechanism underlying the reduced expression of FoxP1 in dying neurons and the mechanism by which FoxP1 maintains the survival of neurons normally. Although almost all studies on FoxP1 have focused on a 90 kDa form of the protein called isoform-A, the brain expresses two other major isoforms – isoforms C and D. The significance of these isoforms as well as other members of the FoxP family that are expressed in the adult striatum will be studied. Finally, we will extend our tissue culture studies to mice and examine whether elevated expression of FoxP1 protects mice from HD and whether the reduced striatal size in brain-specific FoxP1 conditional mice (cKO) is due to neuronal loss. The specific aims of this proposal are: Aim 1: Role of histone deacetylase-3 (HDAC3) in the downregulation of FoxP1 expression in dying neurons. Aim 2: Aim 2: Identify downstream targets of FoxP1 that mediate its protective effect against mut-Htt neurotoxicity. Aim 3: To examine contribution of major FoxP1 isoforms and of FoxP2 and FoxP4 to neuronal survival. Aim 4: Examine the effects of modulating FoxP1 levels on the regulation of neurodegeneration and neuronal survival in vivo. There are currently no effective treatment strategies for the abnormal neuronal loss that occurs in HD. Successful completion of this project has the potential to provide new avenues for the development of a therapy to reduce or stop neurodegeneration in HD.

总结 亨廷顿病（HD）是由CAG异常扩张引起的神经退行性疾病 在亨廷顿基因的第一个外显子中重复，导致具有多聚谷氨酰胺的突变蛋白 扩张.虽然突变亨廷顿蛋白（mut-Htt）在大脑中广泛表达， 神经变性选择性地发生在纹状体中，并且在较小程度上发生在皮质中。我们建议 HD中区域特异性脆弱性的一个关键因素是FoxP 1表达的减少， 一种神经保护蛋白，选择性地在纹状体的中型多刺神经元中表达， 在皮质锥体神经元中相对较低水平。与我们的假设一致，FoxP 1 在HD患者和HD小鼠模型的纹状体中表达降低。FoxP 1表达升高 在培养的神经元中保护它们免受mut-Htt毒性，而敲低其表达诱导 健康神经元的死亡。该提案的总体目标是了解该机制 这是死亡神经元中FoxP 1表达减少的基础，也是FoxP 1 维持神经元的正常存活。尽管几乎所有关于FoxP 1的研究都集中在90 kDa形式的蛋白质称为同种型-A，大脑表达另外两种主要同种型-同种型C和C。 D.这些同种型以及FoxP家族中表达的其他成员的重要性， 将研究成年纹状体。最后，我们将把我们的组织培养研究扩展到小鼠， FoxP 1的表达升高是否能保护小鼠免受HD的影响，以及 脑特异性FoxP 1条件性小鼠（cKO）是由于神经元丢失造成的。本提案的具体目标 目的1：组蛋白去乙酰化酶3（HDAC 3）在凋亡过程中下调FoxP 1表达的作用 神经元目的2：目的2：鉴定FoxP 1的下游靶点，其介导其保护作用， mut-Htt神经毒性。目的3：检查主要FoxP 1亚型和FoxP 2亚型的贡献， FoxP 4对神经元存活的影响目的4：检查调节FoxP 1水平对调节细胞凋亡的影响。 体内神经变性和神经元存活。目前没有有效的治疗策略， HD中发生的异常神经元缺失。该项目的成功完成有可能 为开发减少或阻止HD神经变性的疗法提供了新的途径。