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

Chayan Banerjee,Moumita Roy,Rupsha Mondal,Joy Chakraborty

doi:10.3389/fcell.2020.00727

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.

Highlights

Dysfunctional mitochondria can lead to Cytochrome c release in cytosol and multiple levels of adjustments are required to maintain a healthy mitochondrial population in a normal cell
The current understanding of this dependency suggests that ubiquitin proteasome system (UPS) degrades outer mitochondrial membrane (OMM) proteins and exposes inner mitochondrial membrane (IMM) LC3 receptor – Prohibitin2 (PHB2) (Wei et al, 2017)
The idea in principle suggests that where efficient Parkin mediated ubiquitination is compromised, inhibiting deubiquitinase enzymes (DUBs) might linger the remaining signal which originates from the other routes of mitophagy (SIAH, Mul1, Gp78, etc.)

Summary

INTRODUCTION

Dysfunctional mitochondria can lead to Cytochrome c release in cytosol and multiple levels of adjustments are required to maintain a healthy mitochondrial population in a normal cell. The idea in principle suggests that where efficient Parkin mediated ubiquitination is compromised, inhibiting DUBs might linger the remaining signal which originates from the other routes of mitophagy (SIAH, Mul, Gp78, etc.) These DUBs influence the disease scenario by antagonizing Parkin activity or by modulating UPS and autophagy. Striatum showed increased levels of PHB2, along with PHB1 after rotenone administration (Figure 2B) From these two examples of mitochondrial ETC complex inhibitors, it is clear that different neurotoxins might offer differential alterations of USP14 (and PHB2) in different brain regions. It is always advisable to determine the level of USP14 in the respective brain regions of the animal model, before evaluating the prospects of USP14 inhibition From these experiments it is not clear though whether the increase in USP14 is neuron-specific or not. Impacts the accessibility of the inhibitor to the area, that should negatively impact the outcome after the administration of the inhibitor

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICS STATEMENT