Ubiquitin and ubiquitin-like proteins in the critical equilibrium between synapse physiology and intellectual disability

Post-translational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of Intellectual Disability (ID), a neurodevelopmental disorder that is frequently co-morbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology. SIGNIFICANCE STATEMENT Ubiquitination, sumoylation and neddylation are related PTMs modulating cellular and molecular pathways that are essential to generate fully functional neuronal circuits. Their impairment is indeed implicated in the pathogenesis of several disorders, including ID. Growing evidence now indicates they also functionally cooperate to govern synapse development and function. The main goals of this review are (i) to provide an overview of the current knowledge on the role of ubiquitination, sumoylation and neddylation in synapse functions; (ii) discuss how altered ubiquitination or sumoylation pathways may contribute to ID development; (iii) highlight evidence of a dynamic crosstalk between these PTMs, which represent a novel mechanism that could lead to the identification of new principles underlying synaptic function and dysfunction in ID.