The Ubiquitin-proteasome system in neuroinflammation and neurodegeneration: Molecular insights and therapeutic avenues.

BACKGROUND

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), represent a major and growing public health burden. Neuroinflammation is a critical driver of pathology in these disorders, and the ubiquitin-proteasome system (UPS) has emerged as a central regulator of inflammatory signaling within the nervous system. This review systematically examines the molecular interplay between the UPS and neuroinflammation in the progression of AD and PD.

MAIN BODY: We synthesize the core advances of the past decade in targeting the UPS to modulate neuroinflammation for therapeutic intervention. The UPS, primarily through the specific actions of E3 ubiquitin ligases and deubiquitinating enzymes, exerts precise control over key neuroinflammatory pathways, including NF-κB and the NLRP3 inflammasome, thereby critically shaping the functional states of microglia and astrocytes. In AD, UPS-targeted strategies have evolved beyond the clearance of Aβ and tau to include the reprogramming of microglial phenotype via nodes such as A20 and C/EBPβ. In PD, therapeutic focus has centered on augmenting PINK1/Parkin-dependent mitophagy and on suppressing specific pro-inflammatory factors like Peli1 and USP9X to disrupt pathogenic neuroinflammatory circuits.

CONCLUSIONS

This review provides a focused update on the mechanisms linking UPS dysfunction to neuroinflammation in AD and PD. It highlights the translational potential of targeting specific UPS components to modulate glial cell activation, with particular emphasis on the NF-κB and NLRP3 inflammasome axes as key regulatory hubs for future therapeutic development.