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

基本信息

批准号：
10397597
负责人：
Stewart A Anderson
金额：
$ 22.52万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397597
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

项目摘要

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 缺失综合征 (22qDS) 是 1:4000 出生时最常见的拷贝数变异之一，大约有 25% 的人出现精神分裂症相关症状。由于具有以下特点 22qDS 背景下的精神分裂症 (SZ) 在典型发病方面与非综合征型 SZ 大致相同在青春期后期或成年早期、症状和大脑变化中，22qDS 中的高 SZ 率提供了进行纵向研究的机会，以确定预测精神分裂症风险的认知和生理变化。这样的识别可以导致 22qDS 中 SZ 可变外显率背后的机制研究，并导致预防措施可能适用于某些非综合征性精神分裂症病例。来自人类血液、人类遗传学、IPSC 衍生神经元和小鼠研究的多方面证据模型表明 22qDS 神经表型的各个方面涉及线粒体功能障碍。确实，6 删除区域中的 46 个基因编码线粒体定位蛋白。我们在一项正在进行的研究中发现 IPSC 衍生的神经元在 22+SZ 组中相对于对照组线粒体 OXPHOS 减少（Li 等人） al., 2019)，没有 SZ 的 22q (22q(-)SZ) 组具有 OXPHOS 对照水平。值得注意的是，相对于两者与对照相比，22q+SZ 组中，22q(-)SZ 组多个基因的表达上调参与 OXPHOS 和 PGC1a 的上调，PGC1a 是线粒体生物发生的“主调节器”。这些结果表明 22qDS 中 SZ 的可变外显率可能受到个人能力的影响线粒体补偿，这是一些线粒体遗传病的一个特征。为了用比 IPSC 衍生神经元更高的吞吐量方法来测试这个想法，我们检查了来自 22qDS 成人的 20 个淋巴母细胞系 (LCL)，在 22q+SZ 和 22q+SZ 之间平均分配 22q(-)SZ。通过对 OXPHOS 活性和相关基因表达的一些测量指标进行有针对性的分析，我们发现 22q(-)SZ 组的线粒体复合物 I 活性较高，复合物 1 基因的水平也较高 NDUFV1、PGC1a 及其辅助因子 PPARa。统计分析表明，基于综合“Mito-score” 这 4 项指标对于 22qDS 中是否存在 SZ 相关症状具有超过 90% 的可预测性。这些结果提出了一个引人注目的问题，线粒体补偿失败是否可以在患有 22q11.2 缺失综合征的青少年的淋巴母细胞系预测他们罹患以下疾病的可能性发展成精神分裂症？在此 R21 提案中，利用现有的拼箱线路和现有的纵向跟踪数据，我们寻求确定中青年青少年 LCL 中的线粒体功能/基因表达是否可以预测他们的风险在青少年或年轻人后期出现与 SZ 相关的症状。积极的结果将直接导致旨在预防或改善 22qDS 中 SZ 发展的临床试验，并且可能会对治疗或预防某些非综合征型精神分裂症的影响。