Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases

Neurodegenerative diseases (NDs) are characterized by the aggregation of neurotoxic proteins in the central nervous system. Aberrant protein accumulation in NDs is largely caused by the dysfunction of the two principal protein catabolism pathways, the ubiquitin-proteasome system (UPS), and the autophagy–lysosomal pathway (ALP). The two protein quality control pathways are bridged by ubiquitination, a post-translational modification that can induce protein degradation via both the UPS and the ALP. Perturbed ubiquitination leads to the formation of toxic aggregates and inclusion bodies that are deleterious to neurons. Ubiquitination is promoted by a cascade of ubiquitinating enzymes and counter-regulated by deubiquitinating enzymes (DUBs). As fine-tuning regulators of ubiquitination and protein degradation, DUBs modulate the stability of ND-associated pathogenic proteins including amyloid β protein, Tau, and α-synuclein. Besides, DUBs also influence ND-associated mitophagy, protein secretion, and neuroinflammation. Given the various and critical functions of DUBs in NDs, DUBs may become potential therapeutic targets for NDs.