@article{239ef4fb599d4d0f98b0d544852da864,
title = "cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model",
abstract = "Neuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1Mut)-causing ALS results in mitochondrial damage, thus triggering the release of mtDNA and an RNA:DNA hybrid into the cytosol in an mPTP-independent manner to activate IRF3- and IFNAR-dependent type I interferon (IFN-I) and interferon-stimulating genes. The neuronal hyper-IFN-I and pro-inflammatory responses triggered in ALS-SOD1Mut were sufficiently robust to cause a strong physiological outcome in vitro and in vivo. cGAS/DDX41-STING-signaling is amplified in bystander cells through inter-neuronal gap junctions. Our results highlight the importance of a common DNA-sensing pathway between SOD1 and TDP-43 in influencing the progression of ALS.",
keywords = "Immunology, Neuroscience, Pathophysiology",
author = "Tan, \{Hong Yien\} and Yong, \{Yean Kong\} and Xue, \{Yuan Chao\} and Huitao Liu and Tomomi Furihata and Shankar, \{Esaki Muthu\} and Ng, \{Chen Seng\}",
note = "Funding Information: We thank Tomomi Furihata (Tokyo University of Pharmacy and Life Sciences, Japan), Neil Cashman (University of British Columbia, Canada), Takashi Fujita (Kyoto University, Japan), David Alvarez-Carbonell (Case Western Reserve University, USA), Christine Vande Velde (Universit{\'e} deMontr{\'e}al, Canada), Leigh Anne Swayne (University of Victoria, Canada), and Nelson O. Gekara (Stockholm University, Sweden) for kindly providing valuable materials. H.Y.T. (XMUMRF/2020-C5/ITCM/0003) and K.Y.Y. (XMUMRF/2018-C2/ILAB/0001) is supported by a research grant from Xiamen University Malaysia. T.F. is supported by funding from the Japan Society for the Promotion of Science Kakenhi (\#19K07214). Y.C.X is the recipient of Canadian Institutes of Health Research Doctoral Fellowship. Y.C.X. are recipients of Four-Year Doctoral Fellowships from University of British Columbia. H.L. is the recipient of fellowship from VIROGIN Biotech through Mitacs-Accelerate program. Conceptualization and developed research plan: H.Y.T. Y.K.Y. and C.S.N.; Methodology and Investigation: H.Y.T, Y.K.Y. Y.C.X. H.L. T.F. and C.S.N.; Intellectual input: E.M.S.; Manuscript preparation, writing, review, and editing: H.Y.T. Y.K.Y. E.M.S. and C.S.N. The authors declared that the study was conducted in the absence of any commercial relationships that could be construed as a potential conflict of interest. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank Tomomi Furihata (Tokyo University of Pharmacy and Life Sciences, Japan), Neil Cashman (University of British Columbia, Canada), Takashi Fujita (Kyoto University, Japan), David Alvarez-Carbonell (Case Western Reserve University, USA), Christine Vande Velde (Universit{\'e} deMontr{\'e}al, Canada), Leigh Anne Swayne (University of Victoria, Canada), and Nelson O. Gekara ( Stockholm University , Sweden) for kindly providing valuable materials. H.Y.T. ( XMUMRF/2020-C5/ITCM/0003 ) and K.Y.Y. ( XMUMRF/2018-C2/ILAB/0001 ) is supported by a research grant from Xiamen University Malaysia . T.F. is supported by funding from the Japan Society for the Promotion of Science Kakenhi ( \#19K07214 ). Y.C.X is the recipient of Canadian Institutes of Health Research Doctoral Fellowship. Y.C.X. are recipients of Four-Year Doctoral Fellowships from University of British Columbia . H.L. is the recipient of fellowship from VIROGIN Biotech through Mitacs -Accelerate program. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jun,
day = "17",
doi = "10.1016/j.isci.2022.104404",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier",
number = "6",
}