Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis.

Frédéric Ebstein,Jonas Johannes Papendorf,Elke Krüger,Sébastien Küry

doi:10.3389/fnmol.2021.733012

Abstract

Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

Highlights

Neurodevelopmental disorders (NDD) are a broad spectrum of early onset syndromes affecting the development of the central nervous system (CNS) with a prevalence in children that exceeds 15% worldwide (Romero-Ayuso, 2021)
We have identified 62 reported monogenic neurodevelopmental disorders (NDD) directly caused by lesions in genes encoding components of the ubiquitin-proteasome system (UPS) (Tables 1–5)
20 of them are negative regulators of the two major (i.e., NF-κB and IRF) pathways in inflammation and antiviral response as well as type I IFN signaling (Figure 2). We believe that this number is likely underestimated, as many cellular targets of the identified ubiquitin ligases and/or Deubiquitinating Enzymes (DUB) encompass proteins involved in DNA/RNA processing which may alert the immune system upon dysfunction through the generation of dangers signals

Summary

INTRODUCTION

Neurodevelopmental disorders (NDD) are a broad spectrum of early onset syndromes affecting the development of the central nervous system (CNS) with a prevalence in children that exceeds 15% worldwide (Romero-Ayuso, 2021). It is estimated that approximately 40% of NDD are monogenic conditions predominantly due to lesions of a single gene (Deciphering Developmental, and Disorders, 2017; Brunet et al, 2021), and this figure even rises to about 50% in the case of ID (Kaufman et al, 2010; Karam et al, 2015; Reichenberg et al, 2016; Vissers et al, 2016) Because many of these vulnerable genes do not necessarily encode proteins expressed in the brain with documented functions in neurodevelopment, our current understanding of disease pathogenesis remains extremely limited. Because virtually any gene seems vulnerable, any stage of this process may be impaired from ubiquitin transfer to ubiquitin removal and/or proteasome-mediated breakdown of ubiquitinmodified proteins (Figure 1) These observations clearly point to a cause-and-effect relationship between perturbed UPS function and NDD onset, as discussed below

UBIQUITIN LIGASES IN NDD

UBIQUITIN LIGASES AND PROTEIN AGGREGATION IN NDD

Ubiquitin ligase OMIM Syndrome

Findings

CONCLUSION AND FUTURE DIRECTIONS