Neuroregulatory Mechanisms of PIAS1 and Implications for Huntington's Disease

PIAS1 的神经调节机制及其对亨廷顿病的影响

• 批准号: 8921782
• 负责人: Leslie Michels Thompson
• 金额: $ 56.49万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921782
• 关键词: Acidic Region; Acute; Area; Behavior; Behavioral; Binding; Biochemical; Biological Assay; CAG repeat; Cells; Cognitive; Communication; Complex; Corpus striatum structure; Cultured Cells; Cytokine Signaling; Data; Degradation Pathway; Development; Disease; Disease Progression; Drosophila genus; Employee Strikes; Enzymes; Equilibrium; Functional disorder; Genes; Genetic Transcription; Health; Human; Huntington Disease; Immune response; Inherited; Length; Life; Ligase; Mediating; Modification; Molecular Target; Movement; Mus; Mutate; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Process; Protein Family; Proteins; Publishing; Reporting; Role; Staging; System; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transcriptional Regulation; Transgenic Organisms; Work; base; cellular targeting; design; disease phenotype; drug development; effective therapy; human Huntingtin protein; in vivo; induced pluripotent stem cell; innovation; knock-down; motor impairment; mouse model; mutant; nervous system disorder; neuroinflammation; neuropathology; novel; overexpression; protein folding; protein inhibitors of activated STAT; therapeutic target; transcriptomics; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an inherited neurodegenerative disease that strikes in the prime of life and for which no disease-modifying treatments exist. The disease is caused by the expansion of a CAG repeat within the HD gene, leading to complex and extensive cellular dysfunction. The identification of validated cellular targets that impact the onset and progression of disease and a mechanistic understanding of these targets in HD systems are therefore critical to development of new and effective therapeutics. Mutant HTT (mHTT) and toxic fragments derived from the mutant protein are in a dynamic equilibrium poised to shift the protein homeostatic network from the appropriate balance of protein folding, misfolding, oligomerization and degradation to one in which that balance is disrupted. Upon disruption of this network, cellular proteins accumulate and degradation pathways become impaired. Our studies suggest that the E3 SUMO ligase, PIAS1, is a key modifier of this process and may act as an important regulatory switch in this dynamic equilibrium. In published findings, we identified PIAS1 as a novel modulator of both SUMO-1 and SUMO-2 modification and accumulation of mHTT protein in cultured cells. Further, reduction of the only PIAS in Drosophila delays expression of phenotypes caused by repeat expanded HTT, suggesting this enzyme may provide a selective therapeutic target. In addition to functioning as a SUMO E3 ligase, PIAS is implicated in regulating transcription of several pathways including proinflammatory cytokine signaling and the innate immune response, which is an emerging area of focus in HD. The communication and involvement between E3 SUMO ligases and protein clearance pathways are not well understood with respect to misfolded and accumulated proteins; therefore, understanding the behavior of the PIAS1 network in HD systems will contribute a crucial understanding as to its role in HD pathology. We hypothesize that PIAS1 is a key regulator of HTT SUMOylation and accumulation, that it can modulate HD pathogenesis and that it is a novel target for HD treatments. We propose to use a complementary set of cell based assays and in vivo studies to move forward our mechanistic understanding of PIAS1-mediated networks, and validate PIAS1 as a molecular target for HD drug development. Specifically, we will perform the following aims: Aim 1: Define the PIAS1 network in primary neurons and induced pluripotent stem cells. Aim 2: PIAS1 modulation in HD mouse models. Aim 3: Functional significance of PIAS1 domains in disease modifying pathways.

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传性神经退行性疾病，在生命的黄金时期发作，并且不存在疾病修饰治疗。该疾病是由HD基因内CAG重复序列的扩增引起的，导致复杂和广泛的细胞功能障碍。因此，鉴定影响疾病发作和进展的经验证的细胞靶点以及对HD系统中这些靶点的机制理解对于开发新的有效治疗方法至关重要。突变体HTT（mHTT）和衍生自突变蛋白的毒性片段处于动态平衡，以将蛋白质稳态网络从蛋白质折叠、错误折叠、寡聚化和降解的适当平衡转变为平衡被破坏的平衡。一旦这个网络被破坏，细胞蛋白质就会积累，降解途径就会受损。我们的研究表明，E3 SUMO连接酶，PIAS 1，是这个过程的关键修饰剂，并可能作为一个重要的调节开关，在这个动态平衡。在已发表的研究结果中，我们确定PIAS 1是SUMO-1和SUMO-2修饰以及培养细胞中mHTT蛋白积累的新型调节剂。此外，果蝇中唯一的皮亚斯的减少延迟了由重复扩增的HTT引起的表型的表达，表明这种酶可能提供选择性的治疗靶点。除了作为SUMO E3连接酶发挥作用外，皮亚斯还参与调节几种途径的转录，包括促炎细胞因子信号传导和先天免疫应答，这是HD的一个新兴关注领域。E3 SUMO连接酶和蛋白质清除途径之间的通信和参与对于错误折叠和积累的蛋白质尚未得到很好的理解;因此，了解PIAS 1网络在HD系统中的行为将有助于对其在HD病理学中的作用的重要理解。我们假设PIAS 1是HTT SUMO化和积累的关键调节因子，它可以调节HD发病机制，并且它是HD治疗的新靶点。我们建议使用一组互补的基于细胞的测定和体内研究来推进我们对PIAS 1介导的网络的机制理解，并验证PIAS 1作为HD药物开发的分子靶点。具体来说，我们将执行以下目标：目标1：定义PIAS 1网络在原代神经元和诱导多能干细胞。目的2：HD小鼠模型中的PIAS 1调节。目的3：PIAS 1结构域在疾病修饰途径中的功能意义。