Predicting psychosis in 22q11.2 by failed mitochondrial compensation

通过线粒体补偿失败预测 22q11.2 精神病

• 批准号: 10195202
• 负责人: Stewart A Anderson
• 金额: $ 27.14万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195202
• 关键词: 22q; 22q11.2; Acquired Blindness; Adolescence; Adolescent; Adult; Affect; Biogenesis; Birth; Blood; Blood specimen; Brain; Carrier State; Cell Death; Cell Line; Child; Clinical Trials Design; Clinical assessments; Cognitive; Complex; Copy Number Polymorphism; Data; Development; DiGeorge Syndrome; Diagnosis; Disease; Financial compensation; Gene Expression; Genes; Genetic Diseases; Human; Human Genetics; Individual; Induced pluripotent stem cell derived neurons; Inflammatory; Intercept; Introns; Lead; Longitudinal Studies; Measures; Messenger RNA; Metabolic; Mitochondria; Mitochondrial DNA; Molecular; Mutation; Neurons; Patients; Pattern; Penetrance; Phenotype; Physiological; Prevention; Preventive measure; Production; Proteins; Psychoses; Regulator Genes; Risk; Sampling; Schizophrenia; Statistical Data Interpretation; Symptoms; Teenagers; Testing; Up-Regulation; base; disabling symptom; emerging adult; follow-up; gene function; genetic risk factor; lissencephaly; lymphoblastoid cell line; mRNA Expression; mitochondrial dysfunction; mouse model; predictive test; prevent; relating to nervous system; schizophrenia risk; schizophrenia-spectrum disorder; whole genome; young adult

The 22q11.2 deletion syndrome (22qDS), one of the most common copy number variations at 1:4000 births, is associated with a roughly 25% risk of developing schizophrenia-related symptoms. Since the features of schizophrenia (SZ) in the context of 22qDS are largely shared with non-syndromic SZ in terms of typical onset in later adolescence or early adulthood, symptoms, and brain changes, the high rate of SZ in 22qDS provides an opportunity for longitudinal studies that identify cognitive and physiological changes that predict SZ risk. Such identification can lead to mechanistic studies behind the variable penetrance for SZ in 22qDS, and lead to preventative measures that may extrapolate to some instances of non-syndromic SZ. Multiple lines of evidence, from studies of human blood, human genetics, IPSC-derived neurons, and mouse models, suggest that aspects of the 22qDS neural phenotype involves mitochondrial dysfunction. Indeed, 6 of the 46 genes in the deleted region encode for mitochondrial localizing proteins. We find in an ongoing study of IPSC-derived neurons that while mitochondrial OXPHOS is reduced in the 22+SZ group relative to control (Li et al., 2019), the 22q without SZ (22q(-)SZ) group has control-levels of OXPHOS. Remarkably, relative to both controls and to the 22q+SZ groups, the 22q(-)SZ group has upregulated expression of multiple genes involved in OXPHOS, and upregulation of PGC1a, a "master regulator" of mitochondrial biogenesis. These results suggest that variable penetrance for SZ in 22qDS may be influenced by an individual's capacity for mitochondrial compensation, a feature of some mitochondrial genetic diseases. To test this idea with a far higher throughput approach than possible with IPSC-derived neurons, we examined 20 lymphoblastoid cell lines (LCLs) from 22qDS adults, equally split between those with 22q+SZ and those with 22q(-)SZ. By a targeted analysis of a few measures of OXPHOS activity and related gene expression, we found that mitochondrial complex I activity is higher in the 22q(-)SZ group, as are the levels of the complex 1 gene NDUFV1, PGC1a, and its co-factor PPARa. Statistical analyses revealed that a composite "Mito-score" based on these 4 measures has over 90% predictability for the presence or absence of SZ-related symptoms in 22qDS. These results raise the compelling question, can failed mitochondrial compensation identified in lymphoblastic cell lines from teenagers with 22q11.2 deletion syndrome predict their likelihood of developing schizophrenia? In this R21 proposal, using existing LCL lines and existing longitudinal follow up data, we seek to determine whether mitochondrial function/gene expression in LCLs from mid to younger teenagers predicts their risk of developing SZ-related symptoms as later teenagers or young adults. Positive results would lead directly to a clinical trial designed to prevent or ameliorate the development of SZ in 22qDS, and would likely have implications for the treatment or prevention of some instances of non-syndromic schizophrenia.

22q11.2删除综合征（22qds）是1：4000出生时最常见的拷贝数变化之一，是 与患有精神分裂症相关症状的大约25％的风险相关。由于 在22QD的背景下，精神分裂症（SZ）在很大程度上与非综合SZ共享典型发作 在青春期或成年早期，症状和大脑变化，22QDS中的SZ速率高。 纵向研究的机会，可以识别预测SZ风险的认知和生理变化。这样的 识别可以导致22QD中SZ可变渗透率背后的机械研究，并导致 预防措施可能推断出非综合征SZ的某些实例。 从人类血液，人类遗传学，IPSC衍生的神经元和小鼠的研究中多种证据 模型，表明22QDS神经表型的各个方面涉及线粒体功能障碍。确实，6 已删除区域中的46个基因编码线粒体定位蛋白。我们在正在进行的研究中发现 IPSC衍生的神经元，尽管相对于对照组中的22+Sz组中线粒体oxphos降低（Li Et Al。，2019年），没有SZ（22q（ - ）SZ）组的22Q具有控制级别的Oxphos。非常重要的是，相对于两者 对照和22Q+SZ组，22q（ - ）SZ组具有多个基因的上调 参与OXPHOS和PGC1A的上调，PGC1A是线粒体生物发生的“主调节剂”。 这些结果表明，在22QD中，SZ的可变渗透率可能受个人能力的影响 对于线粒体补偿，某些线粒体遗传疾病的特征。 为了用IPSC衍生的神经元的吞吐量方法测试这个想法，我们检查了 来自22QD成年人的20个淋巴母细胞系（LCLS），同样在22q+Sz的淋巴细胞系中分配 22Q（ - ）SZ。通过对OXPHOS活性和相关基因表达的一些测量的有针对性分析，我们发现 在22q（ - ）SZ组中，线粒体复合物I活性和复合物1基因的水平也更高 NDUFV1，PGC1A及其联合因素PPARA。统计分析表明，基于MITO-SCORE的综合分析 在这4个措施中，对于22QD的存在或不存在与SZ相关的症状的可预测性超过90％。 这些结果提出了令人信服的问题，可能在 来自22Q11.2缺失综合征的青少年的淋巴细胞细胞系预测了它们的可能性 发展精神分裂症？ 在此R21提案中，使用现有的LCL线和现有的纵向后续数据，我们试图确定 线粒体功能/基因表达在中年级到年轻的LCL中是否预测了它们的风险 作为后来的青少年或年轻人，发展与SZ相关的症状。积极的结果将直接导致 旨在预防或改善22QD中SZ的发展的临床试验，并且可能有 对某些非综合精神分裂症的某些实例的治疗或预防。