Roles of Ubiquitin Ligases and Deubiquitylases in Alzheimer's Disease

The mechanisms responsible for the accumulation of Aβ plaques and neurofibrillary tangles, composed of phosphorylated Tau protein, in Alzheimer's disease (AD) remain a mystery. Dysfunction of the ubiquitin-proteasome system (UPS) largely contributes to abnormal protein aggregation. A cascade of ubiquitinating enzymes promotes protein ubiquitination, while deubiquitylases (DUBs) regulate its reversal. Disruptions in ubiquitination and deubiquitination processes result in abnormal protein aggregation and the formation of inclusion bodies, ultimately leading to neuronal damage. Recent studies have highlighted the significant role of protein ubiquitination and deubiquitination in the pathogenesis of AD. E3 ubiquitin ligases, which facilitate protein ubiquitination, are beneficial for Aβ clearance, synaptic function, gap junction maintenance, mitophagy, and neuroinflammation. Conversely, DUBs, responsible for removing ubiquitin from substrate proteins, inhibit Aβ and Tau degradation while promoting neuroinflammation in neurons. This review provides a thorough overview of the involvement of E3 ubiquitin ligases and DUBs in AD, highlighting their diverse roles in aspects of pathophysiological processes.