Autism-Associated Synaptic Protein SYNGAP1 at the Cilium

About This Grant

ABSTRACT Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by substantial genetic and clinical heterogeneity. Although hundreds of high-confidence ASD risk genes have been identified, the underlying biology remains poorly understood and no effective therapeutics currently exist. A key limitation may be the field’s reliance on gene ontology annotations to infer gene function, which has focused attention on synaptic and transcriptional mechanisms, while potentially overlooking other relevant cellular processes. Recent functional evidence from our group and others reveals that many ASD-associated proteins, including those traditionally labeled as synaptic or chromatin regulators, also localize to and function at the primary cilium, a microtubule-based organelle essential for neurogenesis, brain patterning, and neuronal signaling. Our preliminary studies demonstrate that SYNGAP1, a well-characterized postsynaptic Ras GTPase-activating protein and one of the most common monogenic causes of ASD, localizes to cilia and is required for their formation. Furthermore, individuals with SYNGAP1 mutations exhibit reduced nasal nitric oxide, a clinical biomarker of motile cilia dysfunction, suggesting broader systemic involvement. This proposal uses SYNGAP1 as a model to test the central hypothesis that autism-associated genes play pleiotropic roles across subcellular compartments, including functionally significant roles at the cilium across cell types. In Aim 1, we will determine how SYNGAP1 gene dosage affects ciliogenesis and signaling in human neural progenitor cells, before synapses form, with downstream consequences for proliferation, differentiation, and Hedgehog pathway activation. Aim 2 will examine how SYNGAP1 localizes to and regulates local signaling through neuronal primary cilia, including the role of specific domains, isoforms, and GTPase intermediates in modulating ciliary PKA activity and how this changes over synapse maturation. In Aim 3, we will assess the impact of SYNGAP1 loss on motile cilia using human nasal brushings and Xenopus models to evaluate structural and functional consequences, as well as therapeutic entry points given the accessibility and therapeutic tractability of this tissue. This work will advance our understanding of the multifaceted roles of ASD genes and propose an expanded model of autism biology that includes ciliary dysfunction as a key mechanistic contributor. By leveraging the accessibility of airway cilia for biomarker development and therapeutic monitoring, this research offers clinically actionable insights and supports the NIMH mission to uncover the developmental origins of mental illness and improve intervention strategies.