Retrotransposons in Schizophrenia

描述(申请人提供)：精神分裂症(SZ)是一种常见的慢性精神病脑部疾病，影响美国1%的人口，由于相关的残疾、发病率和死亡率，造成了重大的公共卫生问题。SZ的发病机制尚不清楚，但它被认为是一种神经发育障碍。越来越多的神经影像证据表明，SZ的背外侧前额叶皮质功能异常，无论是在激活时还是在休息时。此外，脑电证据已发现SZ的振荡异常，表明小白蛋白阳性的GABA能中间神经元对皮质锥体神经元的调节功能障碍。在过去的5年里，越来越多的数据证明，神经元胚胎发生伴随着LINE1(L1)反转录转座子(RTPs)的激活，达到了意想不到的程度，以至于每个发育中的神经元都可能积累多个从头L1 RTP基因组插入，可能多达80个。这导致了中枢神经系统神经元群体中的大量嵌合体。虽然大多数这些体细胞从头L1 RTP插入对神经元功能的影响不大(可能是因为它们发生在基因沙漠或大内含子中，或者是在细胞功能不需要的基因中)，但有些可能会干扰正常的神经元活动，因为它们插入了特定神经元正常功能所需的基因。如果一个或多个功能性L1RTP插入事件发生在中枢神经系统发育的早期，来自该神经元前体的所有子代神经元也将携带L1插入，可能导致注定要增加SZ风险的神经元功能障碍。这项建议将使用来自SZ患者和匹配对照的CNS组织(在尸检时获得)。利用激光捕获显微切割小白蛋白阳性中间神经元及其前额叶背外侧皮质的靶锥体细胞，然后进行高通量测序，将完成对新的L1RTP插入的检测。通过这种方式，有望发现增加SZ风险的新的体细胞L1RTP插入。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a common, chronic group of psychotic brain disorders, affecting 1% of the US population, creating a significant public health problem because of the associated disability, morbidity and mortality. The pathogenesis of SZ is poorly understood, but it is thought to be a neurodevelopmental disorder. Neuroimaging evidence has accumulated to indicate that the dorsolateral prefrontal cortex functions abnormally in SZ, both when activated and at rest. Further, EEG evidence has identified abnormalities of ¿ oscillations in SZ, suggesting that parvalbumin positive GABAergic interneuron regulation of cortical pyramidal neurons is dysfunctional. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that each developing neuron may accumulate multiple de novo L1 RTP genomic insertions, perhaps as many as ~80. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1 RTP insertions will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional L1 RTP insertion events occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to increase risk for SZ. This proposal will employ CNS tissue (obtained at autopsy) from SZ patients and matched controls. Using laser capture microdissection of parvalbumin positive interneurons and their target pyramidal cells of dorsolateral prefrontal cortex, followed by high-throughput sequencing, detection of novel L1 RTP insertions will be accomplished. In this manner, it is expected that novel somatic L1 RTP insertions, which increase risk for SZ, will be discovered.