Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Abstract

Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and the STING pathway has been implicated in the pathogenesis of further neurodegenerative diseases. To test whether STING activation is sufficient to induce neurodegeneration, we analysed a mouse model that expresses the constitutively active STING variant N153S. In this model, we focused on dopaminergic neurons, which are particularly sensitive to stress and represent a circumscribed population that can be precisely quantified. 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. These neuroinflammatory markers were already elevated in juvenile mice although at this age the number of dopaminergic neurons was still unaffected, thus preceding the degeneration of dopaminergic neurons. More neuroinflammatory markers were blunted in mice deficient for inflammasomes than in mice deficient for signalling by type I interferons. Neurodegeneration, however, was blunted in both mice. Collectively, these findings demonstrate that chronic activation of the STING pathway is sufficient to cause degeneration of dopaminergic neurons. Targeting the STING pathway could therefore be beneficial in Parkinson’s disease and further neurodegenerative diseases.

Pharmacological inhibition of STING signaling attenuates MPTP-induced neuroinflammation and neurodegeneration in mouse parkinsonian models

“…Therefore, our results suggest that the observed neuroprotection of pharmacological blockade of STING in our study may be related with the inhibition of NLRP3 in ammasome-mediated signaling in addition to type I IFN-dependent pathways, although the mechanisms underlying the STING effect on NLRP3 activation are not clearly understood. The results of our work were consistent with a recent study showing that in ammasomes were activated and contributed to STING-mediated neuroin ammation in STINGN153S knock-in mice [10].…”

“…Moreover, mice de cient for the PD-associated proteins PTEN-induced kinase 1 (PINK1) and parkin show a STING-mediated in ammatory phenotype after exhaustive exercise [12]. It is also worth noting that a relatively recent publication by Szego et al reported that STING activation was su cient to induce neurodegeneration by using a genetic mouse model that expresses the constitutively active STING variant N153S [10]. Together these ndings implicate the cGAS-STING pathway in driving the damaging in ammatory processes present in PD, making it an important therapeutic target.…”

“…In a mouse model of Parkin knockout mutants combined with a mtDNA mutator strain, genetic inactivation of STING prevents neuroin ammation, resulting in rescue of neurodegeneration and locomotor de cits [12]. Other recent work showed that STING was upregulated in the SN of PD patients and chronic activation of STING was su cient to induce degeneration of dopaminergic neurons in mice [10]. These ndings strongly implicate that the induction of STING may be a key pathological mechanism that drives PD pathology.…”

“…Many neuroin ammatory diseases, such as ischemic injury, subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), Alzheimer's disease (AD), and PD are characterized by overactivation of the cGAS-STING pathway and expression of type I interferon (IFN) and in ammatory cytokines which underscore pathological progression [6][7][8][9][10][11]. Thus, STING has been recognized as a critical and promising therapeutic target for various neuroin ammatory diseases.…”

STING trafficking as a new dimension of immune signaling

“…Studies within the last 5 yr have associated STING signaling with a wide range of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), PD, as well as several monogenic diseases such as NGLY1 deficiency ( Yang et al, 2018 ) and NPC disease ( Chu et al, 2021 ). Additionally, recent work has demonstrated neuroinflammation and degeneration of dopaminergic neurons in a mouse model of chronic STING activation (SAVI, N153S; Szego et al, 2022 ). Both ligand-mediated (e.g., mitochondrial defect) and trafficking-mediated (e.g., endolysosomal defect) STING signaling mechanisms have been implicated in neurodegenerative diseases.…”