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: 9355237
• 负责人: Stewart A Anderson
• 金额: $ 50.74万
• 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/9355237
• 关键词: 22q11; 22q11 Deletion Syndrome; 22q11.2; Age; Antioxidants; Bioenergetics; Bioinformatics; Birth; Child; Chronic; Complex; Core Protein; 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; Oxidative Phosphorylation; Oxygen saturation measurement; PTGS1 gene; Patients; Phenotype; Prevention; 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; experimental study; gene function; genetic analysis; genetic risk factor; genome editing; high risk; improved; induced pluripotent stem cell; mitochondrial dysfunction; multidisciplinary; neuropsychiatry; novel; novel strategies; oxidative damage; prospective; protein expression; protein function; 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.

代谢损害，包括线粒体功能障碍，可能有助于症状的发展， 精神分裂症然而，探讨线粒体功能障碍、神经元凋亡和脑梗死之间关系的方法尚不成熟。 功能障碍和精神分裂症的风险。精神分裂症最常见的遗传风险因素是 22q11.2缺失综合征（22q11DS），与25%的风险发展这种疾病。有趣的是，在 22 q11 DS大约40个缺失基因中的6个编码线粒体定位蛋白。我们已经组建 一个多学科的团队，联合收割机使用来自22 q11 DS患者的干细胞衍生的神经元， 精神分裂症和对照组，与22q11DS患者和非精神分裂症的遗传分析。我们 将检验22q11DS背景下与乳腺癌相关的基因内的“第二次打击”增加的假设。 神经元代谢功能障碍，并与患者患精神分裂症的风险增加有关。 目标1. 22q11DS源性前脑神经元线粒体功能的研究 将比较来自3组的现有IPSC系：1）22q11DS伴精神分裂症，2）22qDS不伴精神分裂症 精神分裂症或精神病史（并且超过25岁），以及健康对照。前脑样神经元 将比较这些细胞系中线粒体功能障碍的证据， 22q11DS+SZ组。与22q11缺失基因之一是MRPL 40的事实相一致，MRPL 40是22q11缺失基因的亚基。 我们的初步证据表明，来自22q11DS+SZ的IPSC源性神经元 这组人的COX1翻译减少，COX1是一种关键的线粒体DNA编码蛋白。他们也有 显著降低细胞色素C氧化酶活性，以及氧化损伤的有力证据。 目标2.线粒体功能的遗传“二次打击”与22q11DS中的精神病相关吗？ 我们将使用来自大约600名22q11DS患者的全基因组序列数据，平均分配给那些患有22q11DS的患者。 并且没有慢性精神病，来自国际22q11.2DS脑与行为联盟（22QIBBC）。 生物信息学处理将确定22q11DS中发生SZ的风险是否受到潜在影响 由线粒体单倍型组，或与线粒体DNA中突变的存在增加有关，或 与产生线粒体的核编码基因突变的增加有关， 功能蛋白质未来的研究将采用线粒体胞质杂交（“交换”）技术，基因组 编辑，“放回”实验和其他方法来测试目标2中发现的功能相关性， 22q11DS衍生的IPSC中的线粒体功能，并且可以扩展到来自其他高风险SZ的IPSC 组这些结果也可用于检查22q11DS儿童发展的潜在风险。 慢性精神病，使用22QIBBC目前正在招募和研究的大型受试者队列。 这项研究的结果可能会导致改善预测，治疗和预防 22q11DS的精神病，并可推广到22q11DS以外的精神病的治疗或预防。