An insight into the ubiquitin-proteasomal axis and related therapeutic approaches towards central nervous system malignancies

Abstract

The Ubiquitin-Protease system (UPS) is a major destruction system responsible for eliminating dysfunctional/misfolded proteins, thus acting as a pivotal regulator of protein homeostasis in eukaryotic cells. In this review, the UPS system and its various functions in the cell and their detailed impact such as cell cycle control, DNA damage response, apoptosis, and cellular stress regulations have been elucidated with a focus on the central nervous system. Since the Ubiquitin-Protease pathway(UPP) plays a prominent role in the sculpting of the CNS cells and their maintenance, it is naturally deeply involved in many malignancies that develop due to dysregulation of the UPS. Understanding the major disruptive players of the UPS in the development of these malignancies, for example, insoluble protein aggregates or inclusion bodies deposits due to malfunctioning of the UPS has paved the pathway for the development of new therapeutics. Here, the de-regulation of the UPS at various checkpoints in CNS malignancies has been detailed, thus facilitating an easy comprehension of the different targets that remain to be explored yet. The present therapeutic advancements in the field of CNS malignancies management through UPS targeting have also been included thus broadening the scope of drug development. Thus, this review while shedding sufficient light on the details of the UPS system and its connection to CNS malignancies, also opens new avenues for therapeutic advancements in the form of novel targetable UPP proteins and their interactions.

Keywords: Cancer; Central nervous system; Glioblastoma; Therapeutics; Ubiquitin-proteasome system.