Autism spectrum disorder (ASD) is a group of developmental brain disorders with three major symptoms—social impairment, communication difficulties, and repetitive behaviors. According to a survey by the Centers for Disease Control and Prevention (CDC) in 2008, the rate of ASD was around 1 in 88 children. While a specific cause of ASD has yet to be determined, it is well recognized by scientists and physicians that genetic and environmental factors both contribute to the development of ASD. Although early intervention and proper medical care may reduce certain symptoms, no cure for ASD has been found, and innovative therapeutics are highly desired. Phelan-McDermid Syndrome (PMS) is one kind of ASD caused by genetic loss of a gene named SHANK3, accounting for 1% of all ASD cases. In PMS, reducing the level of SHANK3 protein causes abnormality in brain function, resulting in intellectual disability, poor language development, and abnormal socialization. If it were possible to find a way to increase the amount of SHANK3 back to its normal level, this may help ameliorate symptoms in PMS patients. Most proteins are constantly generated and degraded. This process is called protein turnover, the rate of which can be regulated by adding or removing some chemical groups on the protein. For example, adding a phosphate group (a process named phosphorylation) to a protein named guanylate kinase-associated protein (GKAP) at a specific site will cause GKAP to be destabilized and quickly degraded. Considering phosphorylation is one common way to regulate protein stability, SHANK3 stability may be regulated in a similar way. Indeed previous work from revealed that the Shank3 protein is phosphorylated at multiple locations. Phosphorylation is mediated by a group of enzymes called kinases. This project will identify critical kinases that mediate the phosphorylation and determine the stability of Shank3. First, kinases will be identified that directly interact with Shank3. Next, kinases which may affect the stability of Shank3 will be determined. In the last part, these interactions will be validated in neurons. Identification of these critical kinases will contribute to the development of drugs targeting them. These drugs could increase the level of SHANK3 in PMS patients as a direct treatment for this disorder.