Novel SETD5-based Molecular Mechanisms and Therapeutic Tools to Understand and Revert Neuronal Dysfunction Associated with Intellectual disability and Autism

项目总结 自闭症谱系障碍(ASD)通常伴随着智力残疾(ID)，是一组 神经发育障碍通常在儿童的头两岁被诊断出来。社交，情绪化 受影响个人的沟通能力在一生中都受到严重损害，并经常伴随 通过一系列严重程度不同的衰弱症状，包括刻板印象的行为特征， 癫痫发作，感觉过度敏感，运动功能受损，严重干扰他们的日常生活 生命活动。ASD是一个重要的公共卫生问题，因为它影响到54人中的1人。它发生在所有种族中， 种族和社会经济群体，仅在美国，每个儿童每年的估计总成本 在115亿至609亿美元之间。因此，被诊断为ID/ASD儿童的家庭承受着沉重的负担 心理和经济负担。虽然早期干预服务可以显著改善某些方面 在儿童发育方面，目前还没有治疗疾病的方法。尽管付出了巨大的努力，但缺乏 可能是由于我们对潜在的分子和细胞机制缺乏了解。 这些疾病具有极其复杂的病因。不同类型的遗传变异的数量 由于基因组测序技术的进步，与ASD相关的疾病不断增加。然而， 对于这些基因变化如何影响细胞和分子通路，或者是哪种途径，人们仍然知之甚少 脑细胞更容易受到这些突变的影响，这些突变最终会导致与ASD相关的大脑功能障碍。 其中，SETD5基因的功能丧失遗传变异被认为在 基因组的结构和调节神经基因的表达。然而，有一些重要的因素 SETD5控制的分子和细胞通路的知识差距以及ASD相关突变如何 该基因的突变可能导致神经元功能障碍。我们和其他人开始解决这些问题是通过 产生Setd5缺陷小鼠，并显示神经元功能受损和出现类似ASD的行为。 然而，小鼠模型不仅不能准确地概括疾病的病理，而且还不能准确地概括 人类大脑发育的漫长过程。因此，它们可能导致误导性假设。为了补偿 对于这些局限性，我们首次使用人类诱导多能性建立了与SETD5相关的ASD模型 干细胞(HiPSC)。从这些细胞产生神经元，我们像以前一样概括了神经元功能障碍 在小鼠模型中观察。更重要的是，我们发现了导致这种神经元功能障碍的新机制。 特别是，我们发现星形胶质细胞更丰富，是保持神经元健康所必需的 并与大脑相连，可能会产生神经毒性活动。在这项提案中，我们广泛地描述了 参与这一过程的分子和细胞通路，并探索新的治疗靶点，以逆转或 预防SETD5突变引起的神经元功能障碍。这项研究的成功完成将 为星形胶质细胞参与ASD提供了一个前所未有的视角，并有可能使其治疗方法发生革命性变化。

PROJECT SUMMARY Autism spectrum disorder (ASD), which is usually accompanied of intellectual disability (ID), is part of a group of neurodevelopmental disorders that are usually diagnosed during the first two years of age. The social, emotional and communication skills of affected individuals are severely impaired throughout life and are often accompanied by a spectrum of debilitating symptoms with different degrees of severity including, stereotypic behavioral traits, epileptic episodes, sensory oversensitivity, and impaired motor functions that seriously interfere with their daily life activities. ASD is an important public health concern as it affects 1 in 54 individuals. It occurs in all racial, ethnic, and socioeconomic groups, and in the United States alone, the estimated total cost per year per children is between $11.5 and $60.9 billion. Thus, families with ID/ASD-diagnosed children experience heavy psychological and financial burdens. While early intervention services can significantly improve certain aspects of child's development, no disease-modifying treatments are currently available. Despite enormous efforts, lack of effective therapies is likely due to our poor understanding of the molecular and cellular mechanisms underlying these conditions with exceedingly complex etiology. The number of different types of genetic variations associated with ASD keeps increasing thanks to the improvement in genomic sequencing technology. However, there is still little understanding of how these genetic changes impact cellular and molecular pathways or which brain cell are more affected by these mutations that ultimately result in brain dysfunction associated with ASD. Among them, loss-of-function genetic variations in the SETD5 gene, which is believe to play an important role in the structure of the genome and in regulating expression of neuronal genes. However, there are important knowledge gaps on the molecular and cellular pathways controlled by SETD5 and how ASD-related mutations in this gene could contribute to neuronal dysfunction. We and others started to address these questions by generating Setd5 deficient mice and showed impaired neuronal function and appearance of ASD-like behaviors. However, mouse models are limited to accurately recapitulate not only disease pathologies but also the protracted process of human brain development. Thus, they can lead to misleading hypothesis. To compensate for these limitations, we have modeled for the first time SETD5-related ASD using human induced pluripotent stem cells (hiPSC). Generating neurons from these cells we recapitulated neuronal dysfunction as previously observed in mice models. More importantly, we uncovered new mechanisms inducing this neuronal dysfunction. In particular, we found that astrocytes, which are more abundant and necessary for keeping neurons healthy and connected in the brain, might produce neurotoxic activity. In this proposal, we extensively characterize the molecular and cellular pathways involved in this process and explore novel therapeutic targets to revert or prevent neuronal dysfunction induced by SETD5 mutations. The successful completion of this research will provide an unprecedented view of astrocyte involvement in ASD and potentially revolutionize its treatment.