RT Journal Article
SR Electronic
T1 Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.02.478854
DO 10.1101/2022.02.02.478854
A1 Eva M Szegö
A1 Laura Malz
A1 Nadine Bernhardt
A1 Angela Rösen-Wolff
A1 Björn H. Falkenburger
A1 Hella Luksch
YR 2022
UL http://biorxiv.org/content/early/2022/02/04/2022.02.02.478854.abstract
AB The innate immune system can protect against certain aspects of neurodegenerative diseases, but also contribute to disease progression. Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the defense against viral pathogens, activating type I interferon and NF-kB/inflammasome signaling. In order to specifically test the relevance of this pathway for the degeneration of dopaminergic neurons in Parkinson’s disease, we studied a mouse model with heterozygous expression of the constitutively active STING variant N153S.In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. Neuroinflammatory markers were already elevated in juvenile mice, thus preceding the degeneration of dopaminergic neurons. Inflammation and neurodegeneration were blunted in mice deficient for signaling by type I interferons or inflammasomes, but not suppressed completely.Collectively, these findings demonstrate that chronic activation of the STING innate immunity pathway is sufficient to cause degeneration of dopaminergic neurons. This pathway could be targeted therapeutically.Competing Interest StatementThe authors have declared no competing interest.aSynalpha-synucleinCasp1Caspase1cGAScyclic GMP-AMP synthasedsDNAdouble strand DNAGFAPglial fibrillary acidic proteinIba1ionized calcium-binding adapter molecule 1Ifi44interferon induced protein 44IFNinterferonIfnar1interferon alpha receptor1Il-1βinterleukin 1 betaIp-10interferon-gamma induced protein 10 kDIRF3interferon regulatory factor 3ISGinterferon-stimulated genekiknock inMx1interferon-induced GTP-binding proteinNF-kBnuclear factor ’kappa-light-chain-enhancer’ of activated B-cellsNRLP3the nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein 3PDParkinson’s diseaseSAVISTING-associated vasculopathy with onset in infancySNsubstantia nigraSTAT3signal transducer and activator of transcription 3STINGstimulator of interferon genesTHtyrosine hydroxylaseTNFβtumor necrosis factor betaWTwild type