Investigation of degradation mechanisms of Transcription Factor 4 (TCF4), associated with autism spectrum disorders and schizophrenia

Abstract

The TCF4 gene encodes 'Transcription Factor 4 (TCF4)', a bHLH protein important for the regulation of proliferation and differentiation of neural progenitor cells and neuronal function. TCF4 polymorphisms have been associated with several neuropsychiatric disorders, such as autism, schizophrenia, bipolar disorder, and major depressive disorder. Moreover, TCF4 haploinsufficiency results in Pitt-Hopkins Syndrome (PTHS), a neurological genetic disease characterized by severe intellectual disability, absence of speech, delayed cognitive and motor development and dysmorphic features. The mechanisms by which mutations on TCF4 lead to these disorders are still not fully understood. Furthermore, there is no specific therapy for PTHS. Therefore, understanding TCF4 biology is highly relevant for the idealization of new therapeutic approaches. Since PTHS is caused by the lack of the normal amount of TCF4 protein in the cell, a possible pharmacological treatment strategy could be the inhibition of TCF4 degradation. The main cellular mechanism of protein degradation involves the ubiquitin-proteasome system, where ubiquitin chains are added to the target protein, tagging it for degradation by proteasome. In this project, we will use a combination of techniques - including CRISPR library screening and immunoprecipitation - to identify the ubiquitin ligase responsible for TCF4 degradation in vivo. Knowledge about the specific mechanisms of TCF4 protein degradation will allow the development of new therapeutic approaches, contributing not only for PTHS therapy but eventually for the treatment of other neuropsychiatric disorders related to TCF4 as well.