Abstract
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 Statement
The authors have declared no competing interest.
List of Abbreviations
- aSyn
- alpha-synuclein
- Casp1
- Caspase1
- cGAS
- cyclic GMP-AMP synthase
- dsDNA
- double strand DNA
- GFAP
- glial fibrillary acidic protein
- Iba1
- ionized calcium-binding adapter molecule 1
- Ifi44
- interferon induced protein 44
- IFN
- interferon
- Ifnar1
- interferon alpha receptor1
- Il-1β
- interleukin 1 beta
- Ip-10
- interferon-gamma induced protein 10 kD
- IRF3
- interferon regulatory factor 3
- ISG
- interferon-stimulated gene
- ki
- knock in
- Mx1
- interferon-induced GTP-binding protein
- NF-kB
- nuclear factor ’kappa-light-chain-enhancer’ of activated B-cells
- NRLP3
- the nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein 3
- PD
- Parkinson’s disease
- SAVI
- STING-associated vasculopathy with onset in infancy
- SN
- substantia nigra
- STAT3
- signal transducer and activator of transcription 3
- STING
- stimulator of interferon genes
- TH
- tyrosine hydroxylase
- TNFβ
- tumor necrosis factor beta
- WT
- wild type