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.