Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease
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Significance: Huntington disease (HD) is a genetic disorder caused by glutamine-expansion in the huntingtin (mHTT) protein, which affects motor, psychiatric, and cognitive function, but the mechanisms remain unclear. mHTT is known to induce DNA damage and affect autophagy, both associated with inflammatory responses, but what mediates all these were unknown. Here we report that cGAS, a DNA damage sensor, is highly upregulated in the striatum of a mouse model and HD human patient’s tissue. We found ribosomes, which make proteins, are robustly accumulated on the cGAS mRNA in HD cells. cGAS depletion decreases—and cGAS expression increases—both inflammatory and autophagy responses in HD striatal cells. Thus, cGAS is a therapeutic target for HD. Blocking cGAS will prevent/slow down HD symptoms.
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Neuronal cGAS-STING is activated in models of HD and ALS, suggesting that toxic protein aggregates may stimulate DNA release to initiate NFκB activation in neurons.
“Notably, neuronal cGAS‐STING has been shown to be activated in models of HD and ALS, suggesting that toxic protein aggregates may stimulate DNA release (mitochondrial or genomic) to initiate NFκB activation in neurons (Sharma et al, 2020; Yu et al, 2020).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Sharma et al, 2020
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RetractedNeurotoxic reactive astrocytes are induced by activated microglia
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A Chemical Recipe for Generation of Clinical-Grade Striatal Neurons from hESCs
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Self-citationAutophagy side of MB21D1/cGAS DNA sensor
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Induction of pro-inflammatory cytokines by 29-kDa FN-f via cGAS/STING pathway
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The cGAS–STING pathway as a therapeutic target in inflammatory diseases
Decout, A., Katz, J. D., Venkatraman, S., & Ablasser, A. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00524-z · Cited by 2,309 · see citing works
Hou, Y., Wei, Y. Q., Lautrup, S., Yang, B., Wang, Y., Cordonnier, S. A., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2011226118 · Cited by 545 · see citing works
Cellular functions of cGAS-STING signaling
Chen, C., & Xu, P. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.11.001 · Cited by 469 · see citing works
Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice
Xie, X., Ma, G., Li, X., Zhao, J., Zhao, Z., & Zeng, J. (2023) · Nature Aging · doi:10.1038/s43587-022-00337-2 · Cited by 292 · see citing works
Tau Activation of Microglial cGAS–IFN Reduces MEF2C‐mediated Cognitive Resilience
Udeochu, J. C., Amin, S., Huang, Y., Fan, L., Torres, E. R. S., Carling, G. K., Liu, B., McGurran, H., Coronas-Samano, G., Kauwe, G., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01315-6 · Cited by 289 · see citing works
Cytosolic DNA sensing by cGAS: regulation, function, and human diseases
Yu, L., & Liu, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00554-y · Cited by 278 · see citing works
Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide
Li, N., Wang, W., Wenyang, J., Xiong, R., & Geng, Q. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.228 · Cited by 266 · see citing works
STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy
Hinkle, J. T., Patel, J., Panicker, N., Karuppagounder, S. S., Biswas, D., Belingon, B., Chen, R., Brahmachari, S., Pletnikova, O., Troncoso, J. C., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2118819119 · Cited by 240 · see citing works
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Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression
Qiu, S., Zhong, X., Meng, X. L., Li, S., Qian, X., Lu, H., Cai, J., Zhang, Y., Wang, M., Ye, Z., et al. (2023) · Cell Research · doi:10.1038/s41422-023-00788-1 · Cited by 180 · see citing works
Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
Huang, Y., Liu, B., Sinha, S. C., Amin, S., & Gan, L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00672-x · Cited by 164 · see citing works
Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
Welch, G., & Tsai, L. (2022) · The EMBO Reports · doi:10.15252/embr.202154217 · Cited by 129 · see citing works
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Significance of the cGAS-STING Pathway in Health and Disease
Zhou, J., Zhuang, Z., Li, J., & Feng, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713316 · Cited by 121 · see citing works
Mitophagy and cGAS–STING crosstalk in neuroinflammation
Zhou, X., Wang, J., Yu, L., Qiao, G., Qin, D., Yuen-Kwan Law, B., Ren, F., Wu, J., & Wu, A. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.05.012 · Cited by 131 · see citing works
STING trafficking as a new dimension of immune signaling
Jeltema, D., Abbott, K., & Yan, N. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20220990 · Cited by 116 · see citing works
STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?
Smith, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.611347 · Cited by 102 · see citing works
Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases
Okude, H., Ori, D., & Kawai, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.625833 · Cited by 103 · see citing works
Chung, S., Jeong, J.-H., Park, J.-C., Han, J. W., Lee, Y., Kim, J.-I., & Mook-Jung, I. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01295-y · Cited by 103 · see citing works
“However, increasing evidence implicates dysregulation of the cGAS-STING pathway in neurological disorders, including multiple sclerosis 15 , Parkinson ’ s disease 16 , amyotrophic lateral sclerosis (ALS) 17 , Huntington ’ s disease 18 , and recently, amyloidosis 19 and tauopathy 20 .”
Eshraghi, M., Karunadharma, P. P., Blin, J., Shahani, N., Ricci, E. P., Michel, A. M., Urban, N. T., Galli, N., Sharma, M., Ramírez-Jarquín, U. N., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21637-y · Cited by 110 · see citing works
Self-citationThe DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson’s disease
Zhao, M., Wang, B., Zhang, C., Su, Z., Guo, B., Zhao, Y., & Zheng, R. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00767-2 · Cited by 97 · see citing works
Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders
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The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA
Kumar, V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.624597 · Cited by 93 · see citing works
Tang, M., Liu, T., Jiang, P., & Dang, R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105586 · Cited by 81 · see citing works
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DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response
Cinat, D., Coppes, R. P., & Barazzuol, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.729136 · Cited by 78 · see citing works
cGAS–STING, an important signaling pathway in diseases and their therapy
Li, Q., Wu, P., Du, Q., Hanif, U., Hu, H., & Li, K. (2024) · MedComm · doi:10.1002/mco2.511 · Cited by 80 · see citing works
Microglial cGAS drives neuroinflammation in the MPTP mouse models of Parkinson's disease
Ma, C., Liu, Y., Li, S., Ma, C., Huang, J., Wen, S., Yang, S., & Wang, B. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14157 · Cited by 74 · see citing works
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The Complexity of the cGAS-STING Pathway in CNS Pathologies
Fryer, A. L., Abdullah, A. D. I., Taylor, J. M., & Crack, P. J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.621501 · Cited by 65 · see citing works
Gauthier, B. R., & Comaills, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147281 · Cited by 67 · see citing works
The cGAS–STING pathway: more than fighting against viruses and cancer
Bao, T., Liu, J., Leng, J., & Cai, L. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00724-z · Cited by 64 · see citing works
STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges
Yang, K., Tang, Z., Xing, C., & Yan, N. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.014 · Cited by 63 · see citing works
cGAS-STING-mediated IFN-I Response in Host Defense and Neuroinflammatory Diseases
Chen, K., Lai, C., Su, Y., Bao, W. D., Yang, L. N., Xu, P.-P., & Zhu, L.-Q. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210924110144 · Cited by 60 · see citing works
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Relationship between the cGAS−STING and NF-κB pathways-role in neurotoxicity
Zhong, S., Zhou, Q., Yang, J., Zhang, Z., Zhang, X., Liu, J., Chang, X., & Wang, H. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116698 · Cited by 60 · see citing works
STING Signaling and Sterile Inflammation
Couillin, I., & Riteau, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.753789 · Cited by 56 · see citing works
Liu, Y., Zhang, B., Duan, R., & Liu, Y. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.04.009 · Cited by 58 · see citing works
cGAS-STING and neurodegenerative diseases: A molecular crosstalk and therapeutic perspective
Dhapola, R., Paidlewar, M., Kumari, S., Sharma, P., Vellingiri, B., Medhi, B., & HariKrishnaReddy, D. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114902 · Cited by 58 · see citing works
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cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases
Wang, H., Fleishman, J. S., Wu, S., Wang, G., Du, L., Li, J., & Du, J. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102691 · Cited by 53 · see citing works
cGAS‐STING pathway: post‐translational modifications and functions in sterile inflammatory diseases
Hong, Z., Ma, T., Liu, X., & Wang, C. (2021) · FEBS Journal · doi:10.1111/febs.16137 · Cited by 50 · see citing works
Cysteine metabolism and hydrogen sulfide signaling in Huntington’s disease
Paul, B. D. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.05.005 · Cited by 46 · see citing works
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Medicinal chemistry perspective on cGAS-STING signaling pathway with small molecule inhibitors
Tian, X., Xu, F., Zhu, Q., Feng, Z., Dai, W., Zhou, Y.-L., You, Q., & Xu, X. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114791 · Cited by 44 · see citing works
Microglial cGAS–STING signaling underlies glaucoma pathogenesis
Liu, Y., Wang, A., Chen, C., Zhang, Q., Shen, Q., Zhang, D., Xiao, X., Chen, S., Lian, L., Le, Z., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2409493121 · Cited by 45 · see citing works
Ligands stimulating antitumour immunity as the next G-quadruplex challenge
Miglietta, G., Marinello, J., Russo, M., & Capranico, G. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01649-y · Cited by 44 · see citing works
“This is consistent with other findings showing that the cGAS-STING pathway activates the autophagy process through a TANK-binding kinase 1 (TBK1) independent mechanism [108] and that cGAS is a critical regulator of inflammation and autophagy in Huntington’s disease [109].”
ResultMa, Y., Liu, Z., Deng, L., Du, J., Fan, Z., Ma, T., Xiong, J., Xiuyun, X., Gu, N., Di, Z., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05239-y · Cited by 45 · see citing works
Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis
Yu, H., Ren, K., Jin, Y., Zhang, L., Liu, H., Huang, Z., Zhang, Z., Chen, X., Yang, Y., & Wei, Z. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110217 · Cited by 44 · see citing works
Breaking down the cellular responses to type I interferon neurotoxicity in the brain
Viengkhou, B., & Hofer, M. J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1110593 · Cited by 40 · see citing works
Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease
Hruby, A. J., & Higuchi‐Sanabria, R. (2025) · npj Aging · doi:10.1038/s41514-025-00291-4 · Cited by 44 · see citing works
Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within
Luna‐Sánchez, M., Bianchi, P., & Quintana, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168523 · Cited by 40 · see citing works
Yang, G., Fan, X., Mazhar, M., Guo, W., Zou, Y., Dechsupa, N., & Wang, L. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1013706 · Cited by 39 · see citing works
DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease
Wang, Z., Li, Y., Pu, J., & Zhang, B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076313 · Cited by 39 · see citing works
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Ramírez-Jarquín, U. N., Sharma, M., Zhou, W., Shahani, N., & Subramaniam, S. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2107187119 · Cited by 36 · see citing works
Self-citationcGAS-STING and autophagy: crosstalk, molecular mechanisms, and targeted therapy
Wang, Y., Wu, S., Zhang, X., Zheng, W., Wang, Z., Zhang, J., Chen, J., & Wang, H. (2025) · Archives of Toxicology · doi:10.1007/s00204-025-04206-w · Cited by 35 · see citing works
The cytosolic DNA‐sensing cGAS – STING pathway in neurodegenerative diseases
Guo, X., Yang, L., Wang, J., Wu, Y., Li, Y., Du, L.-X., Li, L., Fang, Z., & Zhang, X. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14671 · Cited by 33 · see citing works
He, S., Li, X., Mittra, N., Bhattacharjee, A., Wang, H., Song, S., Zhao, S., Liu, F., & Han, X. (2025) · Advanced Science · doi:10.1002/advs.202410910 · Cited by 34 · see citing works
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Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors
Műzes, G., Barta, B. B., Szabó, O., Horgas, V., & Sípos, F. (2022) · Biomedicines · doi:10.3390/biomedicines10112853 · Cited by 34 · see citing works
Therapeutic approaches targeting aging and cellular senescence in Huntington's disease
Bhat, A. A., Moglad, E. H. O., Afzal, M., Thapa, R., Almalki, W. H., Kazmi, I. A., Alzarea, S. I., Ali, H., Pant, K., Singh, T. G., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70053 · Cited by 32 · see citing works
Autophagy system as a potential therapeutic target for neurodegenerative diseases
Cui, M., Yoshimori, T., & Nakamura, S. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105308 · Cited by 27 · see citing works
Sun, X., Liu, L., Wu, C., Li, X., Guo, J., Zhang, J., Guan, J., Wang, N., Gu, L., Yang, X., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2313652121 · Cited by 27 · see citing works
Al‐Shami, A. S., Elkader, H. A. E. A., Moussa, N., Essawy, A. E., & Haroun, M. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-05039-4 · Cited by 26 · see citing works
Masanneck, L., Eichler, S., Vogelsang, A., Korsen, M., Wiendl, H., Budde, T., & Meuth, S. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239249 · Cited by 25 · see citing works
Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions
Picca, A., Guerra, F., Calvani, R., Romanò, R., Coelho‐Júnior, H. J., Damiano, F. P., Bucci, C., & Marzetti, E. (2022) · Cells · doi:10.3390/cells11040675 · Cited by 26 · see citing works
cGAS, an innate dsDNA sensor with multifaceted functions
Liu, Y., & Xu, P. (2025) · Cell Insight · doi:10.1016/j.cellin.2025.100249 · Cited by 26 · see citing works
Interplay of cGAS with micronuclei: Regulation and diseases
Guo, X., Hintzsche, H., Xu, W., Ni, J., Xue, J., & Wang, X. (2022) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2022.108440 · Cited by 24 · see citing works
Tian, L., Long, G., Zhu, S., Wang, Y., Xu, P., Liu, L., Yao, H., Fang, S., Chen, S., & Li, S. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2427257122 · Cited by 29 · see citing works
cGAS- Stimulator of Interferon Genes Signaling in Central Nervous System Disorders
Li, F., Wang, N., Zheng, Y., Luo, Y., & Zhang, Y. (2021) · Aging and Disease · doi:10.14336/ad.2021.0304 · Cited by 24 · see citing works
Understanding the role of cGAS-STING signaling in ischemic stroke: a new avenue for drug discovery
Chauhan, C., & Kaundal, R. K. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2244409 · Cited by 24 · see citing works
Song, Y., Zhang, Z., Yu, Z., Xia, G., Wang, Y., Wang, L., Peng, C., Jiang, B., & Liu, S. (2021) · Inflammation · doi:10.1007/s10753-021-01412-3 · Cited by 23 · see citing works
Inhibition of cGAS ameliorates acute lung injury triggered by zinc oxide nanoparticles
Jiang, Z., Jiang, Y. L., Fan, J., Zhang, J., Xu, G., Fan, Y., Zhang, L., Qin, X., Jiang, X., Mao, L., et al. (2022) · Toxicology Letters · doi:10.1016/j.toxlet.2022.11.002 · Cited by 23 · see citing works
Lu, Y., Zhao, M., Chen, L., Wang, Y., Liu, T., & Liu, H. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1380517 · Cited by 23 · see citing works
The role of STING signaling in central nervous system infection and neuroinflammatory disease
Fritsch, L. E., Kelly, C., & Pickrell, A. M. (2023) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1597 · Cited by 22 · see citing works
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Biosynthesis of neuroprotective melatonin is dysregulated in Huntington's disease
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- Authors
- Sharma, M., Rajendrarao, S., Shahani, N., Ramírez-Jarquín, U. N., & Subramaniam, S.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Subramaniam, Srinivasa
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-06-24
- Volume
- 117
- Issue
- 27
- Pages
- 15989-15999
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7354937
- OpenAlex
- W3037980935
- Cited by
- 155
- References
- 106
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 27 · 2023: 32 · 2022: 21 · 2021: 28 · 2020: 3
- FWCI
- 9.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01-NS087019-01A1, R01-NS094577-01A1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Huntington's disease, cGAS, huntingtin, polyglutamine expansion, DNA damage recognition, neuroinflammation, autophagy, striatum, therapeutic target
- MeSH terms
- Huntingtin Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Autophagy, Corpus Striatum, Humans, Huntington Disease, Mice, Inbred C57BL, Microtubule-Associated Proteins, Neurons, Nucleotidyltransferases, Phosphorylation, Up-Regulation, Neostriatum, Protein Serine-Threonine Kinases, Mice, Knockout, Chemokine CCL5, Mice, Embryonic Stem Cells, Chemokine CXCL10, Transcriptome
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