| First Author | Hinkle JT | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 15 | Pages | e2118819119 |
| PubMed ID | 35394877 | Mgi Jnum | J:352738 |
| Mgi Id | MGI:7345471 | Doi | 10.1073/pnas.2118819119 |
| Citation | Hinkle JT, et al. (2022) STING mediates neurodegeneration and neuroinflammation in nigrostriatal alpha-synucleinopathy. Proc Natl Acad Sci U S A 119(15):e2118819119 |
| abstractText | In idiopathic Parkinson's disease (PD), pathologic alphaSyn aggregates drive oxidative and nitrative stress that may cause genomic and mitochondrial DNA damage. These events are associated with activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) immune pathway, but it is not known whether STING is activated in or contributes to alpha-synucleinopathies. Herein, we used primary cell cultures and the intrastriatal alphaSyn preformed fibril (alphaSyn-PFF) mouse model of PD to demonstrate that alphaSyn pathology causes STING-dependent neuroinflammation and dopaminergic neurodegeneration. In microglia-astrocyte cultures, alphaSyn-PFFs induced DNA double-strand break (DSB) damage response signaling (gammaH2A.X), as well as TBK1 activation that was blocked by STING inhibition. In the alphaSyn-PFF mouse model, we similarly observed TBK1 activation and increased gammaH2A.X within striatal microglia prior to the onset of dopaminergic neurodegeneration. Using STING-deficient (Stinggt) mice, we demonstrated that striatal interferon activation in the alpha-Syn PFF model is STING-dependent. Furthermore, Stinggt mice were protected from alpha-Syn PFF-induced motor deficits, pathologic alphaSyn accumulation, and dopaminergic neuron loss. We also observed upregulation of STING protein in the substantia nigra pars compacta (SNpc) of human PD patients that correlated significantly with pathologic alphaSyn accumulation. STING was similarly upregulated in microglia cultures treated with alphaSyn-PFFs, which primed the pathway to mount stronger interferon responses when exposed to a STING agonist. Our results suggest that microglial STING activation contributes to both the neuroinflammation and neurodegeneration arising from alpha-synucleinopathies, including PD. |
