Date: Wednesday, March 5, 2025
Location: 46-3002 (Singleton Auditorium)

Speaker: Haitham Amal, PhD
Affiliation: Associate Professor (Tenured), The School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem; Visiting Professor, Boston Children’s Hospital, Harvard Medical School, Harvard University

Host: Dr. Alan Jasanoff

Talk title: The NO Answer for Autism Spectrum Disorder

Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that shares core behavioral deficits. A few molecular mechanisms have been identified in ASD when most of the studies focus on a single pathway/target. To date, no effective single-drug treatment has been found for ASD, which raises the need for new drug targets. We hypothesize that multi-molecular pathways parallelly may lead to synaptic/neuronal dysfunctions and eventually to ASD phenotype. Our multi-proteomic approach using clinical and mouse model samples identified three novel potential targets possibly orchestrating in ASD: (1) de novo S-nitrosylation (NO-mediated protein modification) of the TSC2 protein. In this talk, I will focus on the role of NO (nitric oxide) in ASD. (2) Upregulation of Gephyrin phosphorylation at specific sites, which affects synaptic plasticity and functions. (3) An abnormal upregulation of the catalytic subunit of the mitochondrial ATP synthase, which may affect the integrity of the inner mitochondrial membrane. Here, we used ASD human plasma samples, human induced pluripotent stem cells (hiPSCs), and mouse models to perform a comprehensive study of the mechanisms underlying ASD pathology. The three-way pathological mechanisms were investigated using a state-of-the-art multi-proteomics platform coupled with sophisticated systems biology analyses to filter out ASD-relevant molecular changes. Pharmacological and CRISPR/Cas9 tools were used to validate the targets and explore the molecular and synaptic features following interventions. Three mouse models of ASD (Shank3, Cntnap2, and Nlgn3) were used to evaluate the behavioral outcomes of the pharmacological treatment. This talk will focus on deciphering unknown multi-way molecular mechanisms underlying ASD pathology that may uncover novel drug targets for ASD.