USP14 as a Therapeutic Target Against Neurodegeneration: A Rat Brain Perspective

Abstract

In the recent past, many of the deubiquitinases (DUB) were found to modulate mitochondrial clearance or mitophagy and thus they are currently projected as therapeutic targets against neurodegeneration. Among these DUBs, USP14 stands at a distinctive juncture, since it can influence both proteasome complex activity and autophagy process. USP14 interference can enhance mitochondrial clearance and thus can protect Parkinsonian phenotypes in Drosophila model. However, in higher animal models of neurodegenerative disorders, evaluation of the protective role of USP14 is yet to be done. In this perspective, we pointed out a few of the major considerations that should be classified before designing experiments to evaluate the therapeutic potential of this DUB in rodent models of neurodegeneration. These are mainly: level of USP14 in the concerned brain region and how the level alters in the model system. Because USP14 mediated mitophagy is Prohibitin2 dependent, the anticipated impact of this protein in this aspect is also discussed. To illustrate our view, we show that USP14 levels increases in adult rat brain substantia nigra (SN) and cerebellum compared to the young ones. We also depict that rotenone treatment can immediately lead to increased SN specific USP14 levels. Our perception thus portrays USP14 as a therapeutic target, especially for addressing SN specific neurodegeneration in adult rat brain, but may vary with the disease model.

Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases

“…The ubiquitin-proteasome system (UPS) is often disturbed in many neurodegenerative diseases, demonstrating a potential therapeutic target [ 26 ]. A potential key target within this system are the deubiquitinating enzymes (DUBs), which function to catalyse the cleavage of ubiquitin from target proteins in addition to regulating proteasome activity [ 26 , 180 , 181 ]. Several DUBs have been implicated in the progression of neurodegeneration in a number of animal and cellular models, and are interesting novel therapeutic targets against neurodegeneration as they have been found to induce mitophagy in the absence of parkin/PINK1, in order to prompt mitochondrial clearance.…”

Inhibiting USP14 ameliorates inflammatory responses in trophoblast cells by suppressing MAPK/NF‐κB signaling

“…USP14 is one of the regulators of proteasomal degradation and has been implied to be involved in neurodegenerative disorders and multiple tumor development and progression 11 . For example, USP14 directly influences autophagy and mitophagy in neurons and ultimately affects age‐related neurodegenerative disorders 13 . IU1, an inhibitor of USP14, can increase UPS activities, promote Tau degradation, and enhance mitochondrial elimination in neuronal cells 14–16 .…”

“…11 For example, USP14 directly influences autophagy and mitophagy in neurons and ultimately affects age‐related neurodegenerative disorders. 13 IU1, an inhibitor of USP14, can increase UPS activities, promote Tau degradation, and enhance mitochondrial elimination in neuronal cells. 14 , 15 , 16 Similarly, dysregulation of USP14 has been reported in several tumors, including breast cancer, lung adenocarcinoma, and epithelial ovarian cancer.…”

The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases

“…It enhanced mitophagy by promoting a PINK1/parkin-independent pathway to clear damaged mitochondria, emphasizing its potential in PD treatment [129]. The potential of USP14 inhibitors in PD rodents and key factors to determine the administration regimen have been reported [130].…”