# Lack of functional STING modulates immunity but does not protect dopaminergic neurons in the alpha-synuclein pre-formed fibrils Parkinson’s disease mouse model

## TL;DR

This study shows that STING affects immune responses in a Parkinson's disease mouse model but does not protect brain cells from damage caused by alpha-synuclein.

## Contribution

The study reveals STING's role in modulating immune responses but not in preventing dopaminergic neuron loss in a PD model.

## Key findings

- STING-deficient mice showed more motor changes after alpha-synuclein injection compared to wild-type mice.
- STING deficiency altered microglia and immune responses but did not reduce alpha-synuclein pathology or p62 accumulation.
- Nigrostriatal dopaminergic degeneration was similar in both groups after 6 months, indicating STING is not essential for neuronal loss in this model.

## Abstract

Microglia response is proposed to be relevant in the neurogenerative process associated with alpha-synuclein (α-syn) pathology in Parkinson’s disease (PD). STING is a protein related to the immune sensing of DNA and autophagy, and it has been proposed to be involved in PD neurodegeneration. To investigate this, we injected 10 µg of murine pre-formed fibrils (PFFs) of α-syn (or monomeric and PBS as controls) into the striatum of wild-type (WT) and STINGgt/gt mice, which lack functional STING. We examined motor behavior and brain pathology at 1- and 6-month post-injection. STINGgt/gt mice showed more motor changes associated with PFF injection than WT mice. STINGgt/gt mice had a differential immune response to PFF with early and sustained increased microglia numbers and higher macrophagic CD68 response, but milder changes in the expression of immune-relevant markers such as TLR2, TLR4, IL1ß, and TREM2. However, the lack of STING did not induce changes in the extent of α-syn pathology nor the p62 accumulation seen in the model. Altogether, this resulted in a faster but similar degree of nigrostriatal dopaminergic degeneration after 6 months. Therefore, the data do not support a necessary role for STING in the α-syn-induced nigral neuronal loss in the PFF-PD mouse model used here. However, the results suggest a functional relevance for STING in the brain response to the excess and aggregation of amyloidogenic proteins such as α-syn that can contribute to symptomatic changes.