Predicting psychosis in 22q11.2 by failed mitochondrial compensation

22q11.2缺失综合征（22 qDS）是1：4000出生时最常见的拷贝数变异之一， 与大约25%的精神分裂症相关症状的风险有关。由于特征的 在典型发作方面，22 qDS背景下的精神分裂症（SZ）在很大程度上与非综合征型SZ相同 在青春期后期或成年早期，症状和大脑变化，22 qDS中SZ的高比率提供了 一个纵向研究的机会，确定预测SZ风险的认知和生理变化。等 鉴定可以导致对22 qDS中SZ可变突变率背后的机制研究，并导致 预防措施，可以推断出一些情况下的非综合征SZ。 来自人类血液、人类遗传学、IPSC衍生神经元和小鼠研究的多条证据 模型，表明22 qDS神经表型的方面涉及线粒体功能障碍。事实上，6 缺失区的46个基因编码线粒体定位蛋白。我们在一项研究中发现 IPSC衍生的神经元，而线粒体OXPHOS相对于对照在22+SZ组中减少（Li et 例如，2019），22 q无SZ（22 q（-）SZ）组具有对照水平的OXPHOS。值得注意的是，相对于 对照组和22 q +SZ组中，22 q（-）SZ组多个基因表达上调 参与OXPHOS，并上调PGC 1a，线粒体生物发生的“主调节器”。 这些结果表明，SZ在22 qDS中的可变的迁移率可能受到个体容量的影响 线粒体补偿，这是一些线粒体遗传疾病的特征。 为了用比IPSC衍生神经元高得多的吞吐量方法来测试这个想法，我们检查了 来自22 qDS成人的20个淋巴母细胞样细胞系（LCL），平均分为22 q +SZ和22 q + SZ。 22q（-）SZ.通过对OXPHOS活性和相关基因表达的一些指标进行靶向分析，我们发现， 线粒体复合体I活性在22 q（-）SZ组中较高，复合体1基因水平也是如此。 NDUFV 1、PGC 1a及其辅因子PPARa。统计分析显示，基于“Mito评分”的综合评分 在这4个指标上，对22 qDS中是否存在SZ相关症状的预测性超过90%。 这些结果提出了一个令人信服的问题，线粒体补偿失败是否可以在 来自22q11.2缺失综合征青少年的淋巴母细胞系预测了他们 精神分裂症吗 在本R21提案中，利用现有的拼箱线路和现有的纵向跟踪数据，我们试图确定 中到青少年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SZ相关症状。积极的结果将直接导致 旨在预防或改善22 qDS中SZ发展的临床试验，并且可能具有 对治疗或预防某些非综合征型精神分裂症的影响。

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.