DEUBIQUITINATING ENZYME INHIBITORS AND NEUROPROTECTION

 

Deubiquitinating enzyme (DUB) inhibitors are promising pharmacological interventions for neurodegenerative disorders.

A study by Hu et al has demonstrated that the pan-DUB inhibitor PR-619 has a neuroprotective effect on retinal ganglion cells (RGCs).

PR-619 exerts various biological functions including, induction of autophagy, anti-apoptotic effects, and antitumor properties.

In the experimental glaucoma model of the study, impaired mitophagy was seen in the RGCs.

Parkin is an intricately multifunctional member of the E3 ubiquitin ligase family. It mediates the selective elimination of impaired mitochondria through mitophagy. When mitochondria lose membrane potential, indicating dysfunction or damage, parkin activation and accumulation facilitate mitophagy.

Parkin exerts its ubiquitin-tagging effect upon several proteins present within the mitochondrial outer membrane. These ubiquitinated proteins, bearing Parkin's molecular insignia, serve as beacons of recognition for a host of autophagy receptors and adaptors, among which optineurin emerges as a prominent player.

Evidence shows activated parkin-mediated mitophagy reduces neuronal apoptosis in Parkinson’s and Alzheimer’s diseases.

Dysfunctional mitophagy plays a role in glaucoma pathogenesis.

In vivo, PR-619 increased RGC survival in glaucomatous rats. In vitro, protected RGCs against excitotoxicity and reduced ubiquitin-specific protease (USP) 15 expression.

Additionally, PR-619 upregulated parkin expression, increased LC3-II/LC3-I ratios, and elevated LAMP1 levels, indicating enhanced mitophagy in vivo and in vitro.

Moreover, numbers of mitophagosomes were increased in the optic nerves of PR-619-treated ocular hypertensive rats in vivo.

Prior investigations have substantiated that PR-619 confers neuroprotection to RGCs challenged with glutamate excitotoxicity by augmenting parkin-dependent mitophagy.

Therefore, PR-619 could be a useful strategy for saving RGCs in glaucoma patients.

REFERENCE:

Hu X, Zhang J, Ma H, Lian W, Song W, Du C, Chen S, Wang D, Wei J, Lu Q. The broad-spectrum deubiquitinating enzyme inhibitor PR-619 protects retinal ganglion cell and augments parkin-mediated mitophagy in experimental glaucoma. Sci Rep. 2024;14:24654.