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

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.