# Netrin‐1 Inhibits Neuroinflammation by Modulating DRD2/GSK3β Signaling and Suppressing ROS in a Parkinson's Disease Model

## TL;DR

Netrin-1 protects brain cells in a Parkinson's disease model by reducing inflammation and harmful chemical reactions.

## Contribution

Netrin-1's novel role in modulating DRD2/GSK3β signaling and suppressing ROS in Parkinson's disease is revealed.

## Key findings

- Netrin-1 reduces ROS, α-synuclein phosphorylation, and apoptosis in a rotenone-induced PD model.
- Netrin-1 suppresses pro-inflammatory cytokines and activates DRD2 signaling in dopaminergic neurons.
- Netrin-1 knockout mice show increased neuronal loss and α-synuclein hyperphosphorylation compared to wild-type mice.

## Abstract

Netrin‐1 is stably expressed in mature neurons, where it regulates synaptic plasticity, promotes neuronal survival, and modulates cell adhesion and migration. However, the molecular link between Netrin‐1 and the pathogenesis of Parkinson's disease (PD) has not yet been clearly elucidated.

In this study, we investigated the neuroprotective effects of Netrin‐1 against dopaminergic neuronal death associated with PD pathology.

Here, we show that in a rotenone‐induced cellular model, Netrin‐1 treatment significantly reduced reactive oxygen species (ROS) production, α‐synuclein phosphorylation, and subsequent apoptosis. Moreover, Netrin‐1 suppressed the expression of pro‐inflammatory cytokines, including IL‐6, TNF‐α, and IL‐1β, and promoted the activation of dopamine D2 receptor (DRD2) signaling, which is crucial for dopaminergic neuron survival. Of note, in the Netrin‐1 conditional knockout mouse model, we observed significant dopaminergic neuronal loss, accompanied by increased α‐synuclein hyperphosphorylation at Ser129 and elevated levels of the truncated form of deleted in colorectal cancer (DCC) generated by activated caspase‐3, a marked depletion of DRD2 expression, and hyperphosphorylation of GSK3β at Tyr216. In contrast, these pathological features were attenuated in Netrin‐1 wild‐type (WT) mice. Additionally, the aging process in α‐synuclein (SNCA) transgenic (Tg) mice was characterized by reduced levels of Netrin‐1 and DRD2, alongside increased α‐synuclein accumulation, proinflammatory cytokines, and caspase‐3 activation.

These findings suggest that Netrin‐1 protects dopaminergic neurons by regulating neuroinflammation, preserving DRD2 signaling, and inhibiting phosphorylation of GSK3β at Tyr216, thereby offering potential as a therapeutic agent for dopaminergic neurodegeneration.

A schematic model illustrating how Netrin‐1 supports dopaminergic neuron survival via modulation of DRD2‐mediated signaling in the present study.