Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S, Thacker VV, Favre L, Mangeat B, Kroese LJ, Krimpenfort P, Prinz M, Ablasser A. cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature. 2023 Aug;620(7973):374-380. Epub 2023 Aug 2 PubMed.

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  1. This is a rigorous exploration into the cGAS-STING pathway as a source of neuroinflammation in the aging brain. The findings are likely relevant to age-related neurodegenerative disorders since they complement work from Li Gan’s group, who recently reported that mitochondrial DNA leakage activates cGAS-STING in microglia in the context of tauopathy.

    While this manuscript specifically investigates mitochondrial-derived cytoplasmic DNA as a cGAS-STING activator in the aging brain, other potential sources of cytosolic DNA should be considered. Retrotransposons, for example, can generate new DNA copies that can exist in a cytosolic episomal state. Such elements are increased in the aging brain and in many neurodegenerative contexts. It will be interesting and important to determine the full repertoire of cytoplasmic DNA in the context of aging and age-related neurodegenerative disorders. 

    View all comments by Morgan Lambert

  2. This work from the Ablasser team reveals how cGAS–STING, a ubiquitous senescence pathway sensing exogenous insults, can be activated in the liver by irradiation, in the brain by physiological aging, and in microglia by exposure to mtDNA. Thereby, it contributes to the process of inflammaging and neurodegeneration.

    The functional activation mechanisms of the cGAS–STING complex are convincing and demonstrated by loss of function, via targeted pharmacological inhibition, gain of function, and by ectopic activation of cGAS–STING via a microglial-inducible transgenic mouse line. Using the latter, the authors identify two activated microglia types—DAM-2-MG and the IFN-MG—with distinct inflammatory signatures, which recapitulate AD fingerprints.

    The cGAS-STING pathway is evolutionarily conserved. It is well known for sensing exogenous microbial and cytosolic DNA traces and for triggering immune-protective response mechanism against infectious/pathogenic agents—also called the danger-associated molecular pattern (DAMP) (Cheng et al., 2020; Zheng et al., 2023). It had been shown previously that the cGAS-STING pathway is essential for inducing cellular senescence and an inflammatory phenotype (Yang et al., 2017). 

    Extending the effort of the Ablasser group in identifying small inhibitory molecules of cGAS-STING (Haag et al., 2018), the valuable addition of this in vivo work demonstrates that cGAS-STING pathway activation occurs in microglial cells adopting an inflammatory phenotype similar to that of AD.

    For researchers investigating the infectious etiology of sporadic neurodegenerative diseases, the question remains whether the priming of the cGAS-STING pathway via early infection, or recurrent infections, can sustain chronic low-grade inflammation over a lifetime, which when reactivated by senescence signals can spiral the neuroinflammatory progression of AD.

    As much as the data reported are clean and solid, there is probably more than one mechanism at play, and understanding both the additive and the resilience mechanisms that push or prevent this cascade with age will be crucial.  

    References:

    Cheng Z, Dai T, He X, Zhang Z, Xie F, Wang S, Zhang L, Zhou F. The interactions between cGAS-STING pathway and pathogens. Signal Transduct Target Ther. 2020 Jun 10;5(1):91. PubMed.

    Zheng W, Feng D, Xiong X, Liao X, Wang S, Xu H, Le W, Wei Q, Yang L. The Role of cGAS-STING in Age-Related Diseases from Mechanisms to Therapies. Aging Dis. 2023 Aug 1;14(4):1145-1165. PubMed.

    Yang H, Wang H, Ren J, Chen Q, Chen ZJ. cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4612-E4620. Epub 2017 May 22 PubMed.

    Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, Heymann M, van der Goot FG, Turcatti G, Behrendt R, Ablasser A. Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273. Epub 2018 Jul 4 PubMed.

    View all comments by Lavinia Alberi

  3. This report fits really well with our findings that activation of cGAS-STING, accelerated by tau pathology, represents a converging pathway and a promising therapeutic target for aging-associated neurodegeneration beyond AD (Udeochu et al., 2023). Besides tau, other mitochondrial stresses that accumulate during aging and which may be accelerated by other pathologies, such as TDP-43 dysfunction, could also result in release of mitochondrial DNA into the cytosol. Although direct evidence has been lacking, cytosolic DNA could also result from nuclear DNA damage and genomic instability in aging cells.

    That normal aging is sufficient to induce sufficient cGAS-STING activation to cause cognitive deficits in mice is somewhat surprising, but nevertheless highlights a critical role in aging-associated cognitive decline.

    How does microglia cGAS-STING activation drive cognitive decline? Our study identified loss of neuronal MEF2C, and an associated transcriptional network, as the major mechanism in tauopathy. Whether similar or distinct neuronal mechanisms are involved in aging is an intriguing question, and an exciting one to address next.

    References:

    Udeochu JC, Amin S, Huang Y, Fan L, Torres ER, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GA, Wong MY, Ye P, Nagiri RK, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok SA, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai LH, Sinha SC, Gan L. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci. 2023 May;26(5):737-750. Epub 2023 Apr 24 PubMed.

    View all comments by Li Gan

  4. Aging is associated with loss of cellular resilience and damage to molecules, both of which accumulate over time. This leads to activation of the innate immune system to generate detrimental inflammatory responses that are now considered as critical determinants of neurodegenerative diseases.

    Leveraging earlier established work from the same laboratory that showed the role of the cGAS/STING system of cytosolic DNA recognition in promoting cellular senescence (Glück et al., 2017), Gulen et al. extend its impact and provide a key insight into the link between senescence and neurodegeneration in vivo. They demonstrate that activation of the microglial cGAS/STING pathway is the culprit for low-grade neuroinflammation, neuronal loss, and cognitive deficit, resulting from cytosolic accumulation of DNA derived from perturbed or damaged mitochondria due to aging.

    Interestingly, in mice, autoactivation of the cGAS variant R241E, corresponding to human cGAS R255E, was sufficient to trigger the same neuropathological phenotypes. Since a recent paper on tauopathy reported that microglial mtDNA release and cGAS/STING activity modulate neuroinflammation, the pathway represents a promising therapeutic target to halt neurodegenerative processes (Udeochu et al., 2023). Furthermore, one of the major highlights in the current study is that the authors measured brain penetrance of the STING inhibitor H-151, confirming its ability to reach the brain in mice. Together with other indications of the benefit of H-151 across preclinical models (Haag et al., 2018; Yu et al., 2020), the new data will be foundational to advance this small molecule through to a Phase 1 clinical trial.

    Interesting questions for future studies include if this inflammatory pathway is activated in a similar fashion in other cGAS/STING-expressing cells in aged brain, including neurons and astrocytes. It is possible that molecular events underlying the cGAS/STING-mediated neurodegeneration vary between cell types and conditions. Indeed, while cytokine production is downstream of cGAS/STING activation, the authors reported that TNF-α is the neurotoxic driver in senescent cells, whereas others showed that type I interferons cause tau-associated neurodegeneration (Udeochu et al., 2023).

    STING can be activated independently of cGAS. Could this partly contribute to age-related neurodegeneration if mtDNA release is not the sole trigger? In addition, can low-grade inflammation trigger protein aggregation (or proteinopathy), a pathological hallmark across many neurodegenerative diseases, given that a recent study reported α-synuclein pathology in a STING gain-of-function mouse model (Szego et al., 2022)?

    This study substantially highlights the relationship between cGAS/STING neuroinflammation and age-related neurodegeneration.

    References:

    Glück S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, Bridgeman A, Rehwinkel J, Zender L, Ablasser A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017 Sep;19(9):1061-1070. Epub 2017 Jul 31 PubMed.

    Udeochu JC, Amin S, Huang Y, Fan L, Torres ER, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GA, Wong MY, Ye P, Nagiri RK, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok SA, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai LH, Sinha SC, Gan L. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci. 2023 May;26(5):737-750. Epub 2023 Apr 24 PubMed.

    Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, Heymann M, van der Goot FG, Turcatti G, Behrendt R, Ablasser A. Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273. Epub 2018 Jul 4 PubMed.

    Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RR, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020 Oct 29;183(3):636-649.e18. Epub 2020 Oct 7 PubMed.

    Szego EM, Malz L, Bernhardt N, Rösen-Wolff A, Falkenburger BH, Luksch H. Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice. Elife. 2022 Oct 31;11 PubMed.

    View all comments by Chien-Hsiung (Alan) Yu

  5. This research of the Ablasser lab nicely explores the role of the cGAS-STING signaling pathway in age-related inflammation with subsequent neuronal damage and memory loss. Interestingly, there is a striking accordance with our recently published paper: Van Acker et al., 2023.

    Where Gulen and colleagues showed mitochondria to leak into the cytosol of aged microglia, we showed a similar cGAS-STING activation upon leakage of mtDNA out of dysfunctional lysosomes in a PLD3-linked neuronal model of late-onset Alzheimer’s disease. In line with our results, the Ablasser lab also detected less expression of the lysosomal marker MAC3 when STING was inhibited; pointing to a lysosomal involvement even when lysosomes would not be the primary etiopathology. Also in our neuronal model, we were able to detect a near-restoration of the lysosomal pathology upon STING inhibition, attributed to a lowered mitophagy/autophagy induction. Hence, our paper adds to the data that boosting autophagy alone will unlikely be beneficial in an advanced disease stage, strengthening the idea to target lysosomal catabolism in general.

    How is the autophagic system impacted in the old microglia? Where Gulen and colleagues focus on the inflammatory cascade downstream of STING, STING activation also does promote autophagy. This is of interest given that the authors detect an increase in the ARM/DAM microglia activation state, generally detected around plaques in Alzheimer’s disease. It would be exciting to find out how the autophagic/lysosomal system of these aged microglia are impacted by STING.

    References:

    Van Acker ZP, Perdok A, Hellemans R, North K, Vorsters I, Cappel C, Dehairs J, Swinnen JV, Sannerud R, Bretou M, Damme M, Annaert W. Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism. Nat Commun. 2023 May 24;14(1):2847. PubMed.

    View all comments by Zoë Van Acker

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