IPSC phenotype, mitochondrial haplotype and psychosis in 22q11 deletion syndrome

22q11 缺失综合征中的 IPSC 表型、线粒体单倍型和精神病

• 批准号: 9196885
• 负责人: Stewart A Anderson
• 金额: $ 58.58万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196885
• 关键词: 22q11; 22q11 Deletion Syndrome; 22q11.2; Age; Antioxidants; Bioenergetics; Bioinformatics; Birth; Child; Chronic; Complex; Core Protein; Cytochromes; Data; Development; Disease; Electron Transport; Enrollment; Functional disorder; Future; Genes; Genetic; Genus Hippocampus; Goals; Haplogroup; Haplotypes; International; Investigation; Lead; Mediating; Messenger RNA; Metabolic; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Morphology; Mutation; Neuronal Dysfunction; Neurons; Nuclear; Oxidases; Oxidative Phosphorylation; Oxygen saturation measurement; PTGS1 gene; Patients; Phenotype; Prevention; Process; Prosencephalon; Protein Biosynthesis; Proteins; Psychotic Disorders; Reactive Oxygen Species; Recording of previous events; Ribosomes; Risk; Schizophrenia; Secondary to; Stem cells; Symptoms; System; Technology; Testing; Therapeutic Agents; Translating; Translations; Variant; base; brain behavior; cohort; computerized data processing; conotruncal anomaly face syndrome; cytochrome c oxidase; gene function; genetic analysis; genetic risk factor; genome editing; genome sequencing; high risk; improved; induced pluripotent stem cell; mitochondrial dysfunction; multidisciplinary; neuropsychiatry; novel; novel strategies; oxidative damage; prospective; protein expression; protein function; research study; screening; synaptogenesis; whole genome

Metabolic compromise, including mitochondrial dysfunction, may contribute to the development of symptoms in schizophrenia. However, approaches to explore the relationship between mitochondrial dysfunction, neural dysfunction, and schizophrenia risk are needed. The most common genetic risk factor for schizophrenia is the 22q11.2 deletion syndrome (22q11DS), associated with a 25% risk of developing this disorder. Interestingly, in 22q11DS six of the roughly 40 deleted genes encode for mitochondrial-localizing proteins. We have assembled a multidisciplinary team to combine the use of stem cell derived neurons from 22q11DS patients with or without schizophrenia, and controls, with genetic analyses of 22q11DS patients with and without schizophrenia. We will test the hypothesis that a “second hit” within mitochondrial-related genes in the 22q11DS context increases metabolic dysfunction in neurons and is associated with an increased risk for schizophrenia in patients. Aim 1. Investigation of mitochondrial function in 22q11DS derived forebrain neurons. Existing IPSC lines from 3 groups will be compared: 1) 22q11DS with schizophrenia, 2) 22qDS without schizophrenia or history of psychosis (and over the age of 25), and healthy controls. Forebrain-like neurons from these lines will be compared for evidence of mitochondrial dysfunction that is most pronounced in the 22q11DS+SZ group. Consistent with the fact that one of the 22q11-deleted genes is MRPL40, a subunit of the mitochondrial ribosome, our preliminary evidence suggests that IPSC-derived neurons from the 22q11DS+SZ group have reduced translation of COX1, a key mitochondrial DNA-encoded protein. They also have significantly reduced cytochrome C oxidase activity, and strong evidence of oxidative damage. Aim 2. Are genetic “second hits” to mitochondrial function associated with psychosis in 22q11DS? We will use whole genome sequence data from about 600 22q11DS patients, evenly split between those with and without chronic psychosis, from the International 22q11.2DS Brain and Behavior Consortium (22QIBBC). Bioinformatic processing will determine whether the risk of developing SZ in 22q11DS is potentially influenced by the mitochondrial haplogroup, or is associated with an increased presence of mutations in mtDNA, or is associated with an increased presence of mutations in nuclear-encoded genes that generate mitochondrial- functioning proteins. Future studies would employ mitochondrial cybrids (`swapping”) technology, genome editing, “putback” experiments, and other approaches to test the functional relevance of findings from Aim 2 on mitochondrial function in 22q11DS-derived IPSCs, and could be extended to IPSCs from other high-risk SZ groups. These results could also be used to examine the prospective risk of 22q11DS children to develop chronic psychosis, using the large cohort of subjects currently being enrolled and studied by the 22QIBBC. Significance The results of this study could lead to improved prediction, treatment, and prevention of psychosis in 22q11DS, and could generalize to the treatment or prevention of psychosis beyond 22q11DS.

代谢妥协，包括线粒体功能障碍，可能有助于发展 精神分裂症。但是，探索线粒体功能障碍，神经之间关系的方法 需要功能障碍和精神分裂症风险。精神分裂症最常见的遗传危险因素是 22Q11.2缺失综合征（22q11ds），与患上这种疾病的风险相关25％。有趣的是，在 22q11ds大约40个已删除的基因中的六个编码线粒体定位蛋白。我们已经组装了 一个多学科团队，用于结合使用或没有的22Q11DS患者的干细胞衍生神经元的使用 精神分裂症和对照，对22Q11DS患者和精神分裂症患者进行了遗传分析。我们 将检验以下假设，即在22q11ds上下文中线粒体相关基因中的“第二次命中”增加了 神经元中的代谢功能障碍与患者精神分裂症的风险增加有关。 AIM 1。研究22q11ds衍生的前脑神经元中线粒体功能。 将比较3组的现有IPSC线：1）22Q11D具有精神分裂症，2）22QD 精神分裂症或精神病史（25岁以上）和健康对照。前脑状神经元 从这些线中，将比较线粒体功能障碍的证据，这在 22Q11DS+SZ组。与22q11删除的基因之一是MRPL40的事实一致，MRPL40是一个亚基。 线粒体核糖体，我们的初步证据表明，来自22Q11DS+SZ的IPSC衍生的神经元 组减少了Cox1的翻译，Cox1是一种关键的线粒体DNA编码蛋白。他们也有 显着降低了细胞色素C氧化物活性，并有强烈的氧化物损伤证据。 目标2。与22q11ds中精神病相关的线粒体功能的遗传“第二次命中”吗？ 我们将使用来自约600名22q11ds患者的整个基因组序列数据，甚至在患有 没有慢性精神病，来自国际22q11.2ds的大脑和行为联盟（22QIBBC）。 生物信息学处理将确定在22Q11DS中开发SZ的风险是否受到影响 通过线粒体单倍蛋白组，或与mtDNA突变的存在增加或IS 与产生线粒体 - 功能蛋白质。未来的研究将采用线粒体气缸（“交换”）技术，基因组 编辑，“背包”实验以及其他测试AIM 2的功能相关性的方法 22q11ds衍生的IPSC中的线粒体功能，可以从其他高风险SZ扩展到IPSC 组。这些结果也可以用于检查22q11ds儿童发展的预期风险 慢性精神病，使用当前由22QIBBC招募和研究的大量受试者队列。 显着性这项研究的结果可能会导致改进的预测，治疗和预防 22q11ds的精神病，可以推广到22q11ds之外的精神病的治疗或预防。