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

点击翻译按钮获取中文摘要

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.