Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders...

E3 ligases, essential components of the ubiquitin-proteasome-mediated protein degradation system, play a critical role in cellular regulation. By covalently attaching ubiquitin (Ub) molecules to target proteins, these ligases mark them for degradation, influencing various bioprocesses. With over 600 E3 ligases identified, there is a growing realization of their potential as therapeutic candidates for addressing proteinopathies in cancer and neurodegenerative disorders (NDDs). Recent research has highlighted the need to delve deeper into the intricate roles of E3 ligases as nexus points in the pathogenesis of both cancer and NDDs. Their dysregulation is emerging as a common thread linking these seemingly disparate diseases, necessitating a comprehensive understanding of their molecular intricacies. Herein, we have discussed (i) the fundamental mechanisms through which different types of E3 ligases actively participate in selective protein degradation in cancer and NDDs, followed by an examination of common E3 ligases playing pivotal roles in both situations, emphasising common players. Moving to, (ii) the functional domains and motifs of E3 ligases involved in ubiquitination, we have explored their interactions with specific substrates in NDDs and cancer. Additionally, (iii) we have explored techniques like PROTAC, molecular glues, and other state-of-the-art methods for hijacking neurotoxic and oncoproteins. Lastly, (iv) we have provided insights into ongoing clinical trials, offering a glimpse into the evolving landscape of E3-based therapeutics for cancer and NDDs. Unravelling the intricate network of E3 ligase-mediated regulation holds the key to unlocking targeted therapies that address the specific molecular signatures of individual patients, heralding a new era in personalized medicines.