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While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most\u00a0vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse\u00a0cortical neurons and neurons derived from control human\u00a0induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS\/FTD.<\/jats:p>","DOI":"10.1007\/s00401-024-02688-z","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T16:05:59Z","timestamp":1710345959000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia"],"prefix":"10.1007","volume":"147","author":[{"given":"Christine","family":"Marques","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Held","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Dorfman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon","family":"Sung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amey S.","family":"Kavuturu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek H.","family":"Oakley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Albers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T.","family":"Hyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clotilde","family":"Lagier-Tourenne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3664-7231","authenticated-orcid":false,"given":"Brian J.","family":"Wainger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"2688_CR1","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.stemcr.2020.01.010","volume":"14","author":"M Abo-Rady","year":"2020","unstructured":"Abo-Rady M, Kalmbach N, Pal A, Schludi C, Janosch A, Richter T et al (2020) Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins. 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B.T.H. has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a scientific advisory board or is a consultant for AbbVie, Aprinoia Therapeutics, Arvinas, Avrobio, Axial, Biogen, BMS, Cure Alz Fund, Cell Signaling, Eisai, Genentech, Ionis, Latus, Novartis, Sangamo, Sanofi, Seer, Takeda, the US Dept. of Justice, Vigil, and Voyager.\u00a0His laboratory is supported by research grants from the National Institutes of Health, Cure Alzheimer\u2019s Fund, Tau Consortium, and the JPB Foundation and sponsored research agreements from Abbvie, BMS, and Biogen. L.P. and Mayo Clinic have licensed technology involving <i>C9orf72<\/i> repeat expansion constructs and a virus and AAV-C9orf72-149 repeat expansion mouse model. L.P. is a consultant for Expansion Therapeutics. M.W.A. owns shares and is on the scientific advisory board of Aromha, Inc. He serves on the scientific advisory board of Sudo Therapeutics and is a consultant for BMS and Transposon. C.L.T. serves as a scientific advisory board member or is a consultant for Arbor Biotechnology, Dewpoint Therapeutics, Libra Therapeutics, Mitsubishi Tanabe Pharma Corporation, Sanofi, and SOLA Biosciences.\u00a0B.J.W. serves as a scientific advisory board member and a consultant for Quralis and is a consultant for Apic Bio, Q-State Biosciences, Takeda, and Sanofi. The remaining authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"56"}}