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: 8987967
• 负责人: Beverly L. Davidson
• 金额: $ 46.53万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987967
• 关键词: Acidic Region; Acute; 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; Equilibrium; Functional disorder; Genes; Genetic Transcription; Human; Huntington Disease; Immune response; Implant; Inherited; Knockout Mice; Life; Ligase; Longitudinal Studies; Mediating; Microglia; Modification; Molecular; Molecular Target; Movement; Mus; Mutate; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Protein Family; Proteins; Publishing; Reporting; Role; Staging; System; Testing; Therapeutic Intervention; Toxic effect; Transcriptional Regulation; Virus; Work; base; biophysical analysis; cellular targeting; design; disease phenotype; drug development; human Huntingtin protein; in vivo; induced pluripotent stem cell; innovation; knock-down; motor impairment; mouse model; mutant; nervous system disorder; neuroinflammation; neuropathology; neuroprotection; novel; overexpression; protein folding; protein inhibitors of activated STAT; public health relevance; research study; 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 has no disease-modifying treatment. HD is caused by CAG repeat expansion in the HD gene, causing complex and extensive cellular dysfunction. The identification of cellular targets that impact disease onset and progression and enlighten further mechanistic understanding of these targets are critical for development of new treatments. Mutant HTT (mHTT) and toxic fragments derived from the mutant protein are in a dynamic equilibrium poised to shift the homeostatic network from the appropriate balance of protein folding, misfolding, oligomerization and degradation to one in which that balance is disrupted. Upon network disruption, cellular proteins accumulate and degradation pathways become impaired. Our studies suggest that the E3 SUMO ligase, PIAS1, may be 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 and that reduction of PIAS in Drosophila delays phenotypes caused by repeat expanded HTT. In recent preliminary data, we find that reduction of PIAS1 expression in R6/2 mice confers robust neuroprotection, suggesting PIAS may provide a selective therapeutic target. The communication and involvement between E3 SUMO ligases and protein clearance pathways are not well understood with respect to misfolded and accumulated proteins. In addition to functioning as a SUMO E3 ligase, PIAS is implicated in regulating transcription of proinflammatory cytokine signaling and innate immune response pathways. Therefore, clarifying the PIAS1 network in HD systems will provide 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 may be a novel target for development of HD therapies. We propose to use cell based assays and in vivo studies to advance our mechanistic understanding of PIAS1-mediated networks, and validate PIAS1 as a molecular target for HD drug development. Specifically we will carry out the following proposed aims: Aim 1: PIAS1 modulation in HD mouse models. Aim 2: PIAS1 network in mHTT expressing neural cells. Aim 3: In vivo effects of mHTT expression in heterozygous PIAS1-null mice. Aim 4: Functional significance of PIAS1 domains in disease modifying pathways.

 描述（由申请人提供）：亨廷顿病（HD）是一种遗传性神经退行性疾病，在生命的黄金时期发作，没有疾病修饰治疗。HD是由HD基因中的CAG重复扩增引起的，引起复杂和广泛的细胞功能障碍。识别影响疾病发作和进展的细胞靶点并启发对这些靶点的进一步机制理解对于开发新治疗至关重要。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。一旦网络中断，细胞蛋白质积累，降解途径受损。我们的研究表明，E3 SUMO连接酶，PIAS 1，可能是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，并且果蝇中皮亚斯的减少可以延迟由重复扩增的HTT引起的表型。在最近的初步数据中，我们发现R6/2小鼠PIAS 1表达的减少赋予了强大的神经保护作用，这表明皮亚斯可能提供了一个选择性的治疗靶点。E3 SUMO连接酶和蛋白质清除途径之间的通信和参与还没有很好地了解错误折叠和积累的蛋白质。除了作为SUMO E3连接酶起作用外，皮亚斯还参与调节促炎细胞因子信号传导和先天免疫应答途径的转录。因此，阐明PIAS 1网络在HD系统中的作用，将提供一个至关重要的理解，其在HD病理。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，并且它可能是开发HD治疗的新靶点。我们建议使用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。具体而言，我们将实现以下提出的目标：目标1：HD小鼠模型中的PIAS 1调节。目的2：PIAS 1在mHTT表达神经细胞中的网络。目的3：mHTT表达在杂合PIAS 1缺失小鼠中的体内作用。目的4：PIAS 1结构域在疾病修饰途径中的功能意义。