NExT NDD-UBIPRO - Frédéric Ebstein (2022 - 2025)

Frédéric Ebstein is the scientific leader of a NExT Talents project entitled : Elucidating the pathogenesis of neurodevelopmental disorders caused by disturbances in the ubiquitin-proteasome system
 

Summary

In eukaryotic cells, protein homeostasis is maintained by the ubiquitin-proteasome system (UPS), which tags damaged and/or unwanted proteins with ubiquitin molecules prior to their degradation into peptides by 26S proteasomes. Any disruption of this process potentially affects protein recycling and has pathological consequences for the cell. This is particularly well illustrated in neurodevelopmental disorders (NDD), a group of rare, early-onset syndromes frequently caused by loss-of-function mutations in genes encoding UPS components such as proteasome subunits, ubiquitin hydrolases or ubiquitin ligases. Our recent research has revealed that NDD caused by genomic alterations in UPS genes is systematically associated with immune dysregulation and in particular with the acquisition of a type I interferon (IFN) genetic signature. However, the molecular basis and contribution of these type I IFN responses to the pathogenesis of NDD remain poorly defined.
 

Objectives

Our main objective in this project is therefore to understand the immunological component of NDD and to elucidate the causal relationship between UPS dysfunction and the triggering of sterile inflammation. In this respect, we will focus in particular on identifying immunostimulatory “danger signals” specifically generated in NDD using multi-omics strategies. Using a CRISPR/Cas9 mini-library screening approach, we will also attempt to determine how these signals are integrated by the innate immune system. We will then use patient-derived induced pluripotent stem cells (iPSCs) to determine the impact of autocrine and/or paracrine inflammation on neurogenesis and basic neuronal functions, including synaptic transmission.
A corollary objective of this project is dedicated to the development of diagnostic tools for the rapid recognition and detection of UPS dysfunction in biological samples, including prenatal samples. More specifically, we will design assays based on the use of cell-permeable fluorescent probes that react with functionally active forms of various UPS enzymes or with quaternary structures typically present in aggregated proteins.
Finally, our third and last objective is to address the question of whether UPS function can be restored in NDD patients. To do this, we will screen a mini-library of compounds customised for their ability to remove protein aggregates and suppress type I IFN signalling in patient-derived cells.

Expected results

From these data, we hope to obtain a more integrated picture of the pathophysiology of UPS dysfunction and identify new biomarkers and therapeutic targets, not only for NDD caused by UPS variants, but also for neurological disorders.