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，发病于年富力强，目前尚无缓解疾病的治疗方法。 HD 是由 HD 基因中的 CAG 重复扩增引起的，会导致复杂而广泛的细胞功能障碍。识别影响疾病发生和进展的细胞靶点并进一步了解这些靶点的机制对于开发新疗法至关重要，突变蛋白衍生的毒性片段处于动态平衡状态。将稳态网络从蛋白质折叠、错误折叠、寡聚和降解的适当平衡转变为平衡被破坏的平衡，我们的研究表明，E3 SUMO 连接酶 PIAS1 会发生积累和降解途径受损。在已发表的研究结果中，我们确定 PIAS1 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。在最近的初步数据中，我们发现 R6/2 小鼠中 PIAS1 表达的减少赋予了强大的神经保护作用，这表明 PIAS 可能提供选择性治疗靶标 E3 SUMO 连接酶之间的通讯和参与。对于错误折叠和积累的蛋白质，蛋白质清除途径尚不清楚。 除了作为 SUMO E3 连接酶发挥作用外，PIAS 还参与调节促炎细胞因子信号转导的转录。因此，阐明 HD 系统中的 PIAS1 网络将有助于了解其在 HD 病理学中的作用，我们发现 PIAS1 是 HTT SUMO 化和积累的关键调节因子，它可以调节 HD 发病机制。它可能是开发 HD 疗法的新靶标。我们建议使用基于细胞的测定和体内研究来推进我们对 PIAS1 介导的网络的机制理解，并验证 PIAS1 作为 HD 药物的分子靶标。我们将实现以下拟议目标： 目标 1：HD 小鼠模型中的 PIAS1 调节 目标 2：表达 mHTT 的神经细胞中的 PIAS1 网络 目标 4：mHTT 表达对杂合 PIAS1 小鼠的体内影响。 ：PIAS1 结构域在疾病修饰途径中的功能意义。