Predicting psychosis in 22q11.2 by failed mitochondrial compensation

22q11.2缺失综合征(22qDS)是出生时1：4000最常见的拷贝数变异之一， 与大约25%出现精神分裂症相关症状的风险有关。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性SZ大体相同 在青春期后期或成年期早期，症状和大脑变化，22qDS中SZ的高比率提供了 这是一个纵向研究的机会，可以确定预测SZ风险的认知和生理变化。是这样的 识别可以导致22qDS中SZ变量外显率背后的机制研究，并导致 可推断为某些非综合征型SZ的预防措施。 来自对人类血液、人类遗传学、IPSC来源的神经元和小鼠的研究的多种证据 模型表明，22qDS神经表型的某些方面涉及线粒体功能障碍。事实上，其中6个 缺失区域的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来源的神经元，而线粒体OXPHOS在22+SZ组相对于对照组(Li ET)减少 等，不含SZ的22q组(22q(-)SZ)具有OXPHOS的控制水平。值得注意的是，相对于两者 与对照组和22q+SZ组相比，22q(-)SZ组多个基因表达上调 参与OXPHOS，以及上调线粒体生物发生的“主调节器”PGC1a。 这些结果表明，SZ在22qDS中的变量外显度可能受个体能力的影响 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来源的神经元高得多的吞吐量方法来测试这一想法，我们检查了 来自22qDS成人的20个淋巴母细胞样细胞系(LCL)，平均分为22q+SZ组和22q+SZ组 22Q(-)SZ。通过对OXPHOS活性和相关基因表达的几个指标的有针对性的分析，我们发现 22q(-)SZ组线粒体复合体I活性较高，复合体1基因水平也较高 NDUFV1、PGC1a及其辅助因子PPARa。统计分析显示，一个综合的“Mito-Score”基于 在这4项指标上，对22QDS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，线粒体补偿失败能否在 22q11.2缺失综合征青少年的淋巴母细胞株可预测其发生 罹患精神分裂症？ 在这份R21提案中，使用现有的LCL线路和现有的纵向跟踪数据，我们试图确定 中青年LCLS的线粒体功能/基因表达是否可以预测他们患上糖尿病的风险 在青少年或青壮年后期出现SZ相关症状。积极的结果将直接导致 临床试验旨在预防或改善22QDS中SZ的发展，并可能 对某些非综合征型精神分裂症的治疗或预防的启示。

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.