Translational investigation of Neurodevelopmental Disorders caused by impairment of the Ubiquitin-Proteasome System – UPS-NDDecipher

The ubiquitin-proteasome system (UPS) is one of the major eukaryotic pathways for intracellular degradation of proteins which are misfolded, oxidized, damaged and/or no longer needed. Denatured proteins to be degraded are specifically tagged with ubiquitin chains before being addressed to the 26S proteasome that ensure their hydrolysis. The UPS is essential to neuronal development and function and most of the approximately 1,200 genes which contribute to this protein degradation pathway are highly expressed in brain. Their pathogenic variants are responsible for about 10-15% of neurodevelopmental disorders (NDDs). Yet, since the recognition of UPS-related NDDs (UPS-NDDs) is fairly recent, virtually nothing is known about how UPS genetic variants can lead to abnormal brain development.

The UPS-NDDecipher project was designed to address this question. Its objective is to decipher the physiopathological mechanism of six UPS-NDDs caused by pathogenic genetic variants in USP7, CUL4B, PSMD12, PSMC3, PSMC5 or BAP1. The transdisciplinary approach followed in the project will combine state-of-the-art methods in cell reprogramming and differentiation, neuroimaging and functional genomics applied to patient cells. The implementation of the project is made possible by the contact network with clinical geneticists, scientists and patient organizations that was previously established by members of the UPS-NDDecipher consortium and allowed the initiation of a biocollection dedicated to UPS-NDDs. The occurrence of morphological abnormalities will be monitored during differentiation of patient induced pluripotent stem cells (hiPSC)-derived glutamatergic neurons and culture of mouse hippocampal cell lines. In addition, a specific molecular signature of UPS-NDDS will be sought by comparative integrative multi-omics analysis of patient and isogenic hiPSC-derived neuronal lines. Once a molecular signature specific to the six UPS-NDDs has been identified, selected active compounds will be tested for their ability to restore a normal UPS protein degradation in mutant cells. The ultimate goal of the project is thus to open the way to pre-clinical studies and hopefully to offer therapeutic perspectives to patients.