Autism spectrum disorder (ASD) is a highly heterogeneous constellation of neurodevelopmental conditions characterized by impaired language and communication skills, social behavior abnormalities, and stereotypic patterns of behavior. ASD affects more than 1% of the population with a societal and economic burden exceeding $150 billion a year. Advances in genomics are unraveling the complex genetic architecture of ASD, however our understanding of the molecular mechanisms underlying the disorder is lagging behind. Pathogenic mutations in the gene encoding an E3 ubiquitin ligase, UBE3B, have been recently identified in individuals with either ASD or ID, yet the mechanism(s) of how these mutations disrupt normal brain development and function are completely unknown. Our preliminary data identified a role for UBE3B in regulating the highly conserved branched-chain amino acid (BCAA) metabolism pathway. UBE3B could provide an entryway into studying disease mechanism underlying ASD, specifically in patients with defects in the BCAA metabolism pathway. This proposal aims to dissect the role of the BCAA metabolism pathway in ASD, through the study of UBE3B function in vivo. We will determine the role of UBE3B in BCAA metabolism by deleting Ube3b specifically in the brain (Ube3b cKOBrain) or the liver (Ube3b cKOLiver), and analyzing these conditional knockout mice in a series of biochemical and behavioral experiments. Results from our studies will enable us to determine whether the neurological phenotype in patients with UBE3B mutations is primarily due to a metabolic defect in the brain or the liver. Our work will lay the groundwork for targeted therapies for ASD, specifically in patients who carry pathogenic mutations in UBE3B, BCKDK, DBT, or genes encoding other components of the BCAA metabolism pathway. It will provide mechanistic understanding in a very complex, debilitating, and intractable disorder.
Autism spectrum disorder (ASD) is a highly complex group of debilitating neurological conditions affecting development in over 1% of the population. In order to develop effective therapies, we need to first understand the molecular mechanisms and pathways responsible for disease development. Our proposed studies will uncover how genetic mutations alter brain function in ASD with an ultimate goal of developing new treatment strategies for patients with ASD and other neurodevelopmental disorders.
