Ubiquitin Proteasome System in Schizophrenia

Summary The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. It influences neurogenesis, synaptogenesis and neurotransmission by determining the localization, interaction and turnover of scaffolding, presynaptic and postsynaptic proteins. Moreover, UPS signalling transduces epigenetic changes in neurons independent of protein degradation and as such dysfunction of components and/or substrates of this system have been linked to a broad range of brain conditions. Although links between UPS dysfunction and neurodegenerative disorders have been known for some time, only recently have similar links emerged for neurodevelopmental disorders, such as schizophrenia. We and others have found that diffeerent components of the UPS are dysregulated in schizophrenia. The project aims to investigate whether specific poly-ubiquitin changes are altered in brain samples from individuals with schizhophrenia.

Project Details

Our results suggest that ubiquitinated protein formation may be abnormal in the brain of those with schizophrenia. Therefore, a derangement in protein ubiquitination may be linked to pathogenesis or neurotoxicity in schizophrenia. Further studies of the UPS components are warranted in schizophrenia to better understand how this pathway is involved in this brain disorder. Post mortem human brain samples from the orbital frontal cortex will be homogenized and centrifuged to collect protein supernantants. Levels of poly-lysine-48 and poly-lysine-63 ubiquitin chains will be detected by Western blot.