# Mechanisms of Programmed Cell Death in Sodium Iodate-Driven Retinal Degeneration and the Role of DJ-1

## TL;DR

This study explores how retinal cells die due to oxidative stress and finds that the protein DJ-1 plays a key role in regulating this process.

## Contribution

The paper reveals that DJ-1 deficiency increases apoptosis and necroptosis in retinal degeneration caused by sodium iodate.

## Key findings

- DJ-1 knockout mice showed increased JNK1/2 activation and FOXO1 levels after sodium iodate injection.
- Caspase-3 and pMLKL activity was higher in DJ-1 knockout retinas compared to controls.
- Necroptosis inhibitors reduced retinal degeneration in both DJ-1 knockout and wild-type mice.

## Abstract

Oxidative stress-induced RPE cell death is a major cause of AMD pathogenesis. However, the exact modes of oxidative stress-driven retinal death remain elusive. To address this knowledge gap, we investigated the role of DJ-1, an antioxidant protein we previously characterized in the retina, in cell death regulation. Specifically, we analyzed cell death pathways in the retinas of DJ-1 knockout (KO) mice, with or without sodium iodate (NaIO3) injection. We quantified MAPK signaling protein activation by Western blot. The distribution of the cell death executioners, activated caspase 3, and pMLKL, was investigated. The effects of caspase and necroptosis inhibitors in mice previously injected with NaIO3 were determined. Significant increases in JNK1/2 activation and FOXO1 levels were detected in RPE lysates when DJ-1 KO mice were injected with 10 mg/kg NaIO3. The immunoreactivity of active caspase-3 and pMLKL was stronger in the retinas of DJ-1 KO compared with C57BL mice. These immunoreactivities further increased in the degenerating outer retina post NaIO3 injection and were stronger in the retina of DJ-1 KO compared with C57BL mice at both doses of NaIO3. ZVAD treatment rescued retinal degeneration to varying degrees in DJ-1 KO mice. However, necrostatin (Nec-1) alleviated retinal degeneration in both DJ-1 KO and C57BL mice, suggesting that apoptosis is a major cell death modality in the absence of DJ-1. Overall, oxidative stress-induced RPE and retinal cell death involve activation of both apoptosis and necroptosis in the absence of DJ-1.