Protein turnover in the nervous system: ubiquitin ligase UBE3A
At a fundamental level, the function of the brain is dictated by its molecular content. Yet, the molecules that comprise the brain are inherently unstable, and integral components such as proteins are continually turned over and replaced by newly synthesized ones. How does information endure in the face of such volatility? And what happens when the brain can no longer cope with this instability? The goal of my research is to gain a comprehensive understanding of protein turnover in the nervous system: how this process is regulated, how it influences the integrity of the nervous system, and ultimately, how dysfunction in protein degradation contributes to disease. My work is focused currently on the ubiquitin ligase UBE3A. The compelling reason to study this enzyme is that changes in its activity underlie numerous neurological disorders. Loss-of-function of UBE3A causes a severe form of mental retardation known as Angelman syndrome, whereas its gain-of-function is strongly linked to Autism, schizophrenia, and mood disorders. Moreover, UBE3A activity gradually diminishes in the cortex with age, suggesting strict regulation of its activity throughout a lifetime. Using mouse models, my work employs a multidisciplinary approach to construct a comprehensive picture of how changes in the molecular content of neurons alter their physiological properties. The ultimate goal of this work is to provide new fundamental insights to inform therapeutic strategies for disorders of the central nervous system. Given the intricate link between protein degradation and neurodegeneration, this work promotes the mission of the Hope Center to discover common fundamental mechanisms that underlie neuronal death and repair.