Deubiquitinating enzymes at the crossroads of blood–brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions

The ubiquitin-proteasome system (UPS) carries immense significance concerning cellular homeostasis that encompasses both ubiquitination and deubiquitination as key facets for maintaining protein stability. The deubiquitinating enzymes (DUBs) have emerged as critical regulators of proteostasis, neuroinflammation and blood-brain barrier (BBB) integrity by controlling the fate of crucial proteins associated with barrier architectures in CNS and neurodegenerative disorders (NDs) alike. However, a concrete understanding of their specific neurodevelopmental and neuroprotective functions is yet to be discerned. This article discusses the multifaceted roles of DUBs in the maintenance of BBB integrity, neuroprotection and various NDs and also underscores the therapeutic prospects targeting the same. While DUBs like USP7, USP9X, USP27X, UCHL1, etc. participate in neural stem cell maintenance and neurogenesis, including BBB function, USP13, USP14, USP25, BRCC3 and CYLD, among others, are associated with BBB dysfunction and NDs. The mechanistic underpinning concerning their hitherto unexplored mode of action, DUB-substrate interactions and specificity would facilitate developing the therapeutic agonists and small-molecule inhibitors to prevent or reverse neuroinflammation, BBB impairment and developmental disorders. Recent innovations concerning DUB-targeting chimaeras (DUBTACs) and proteolysis-targeting chimaeras (PROTACs) can be explored further for their plausible administration via nanoparticle-based delivery approaches to alleviate the progressive neurodegeneration.