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TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS
Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is drive...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599077/ https://www.ncbi.nlm.nih.gov/pubmed/33031745 http://dx.doi.org/10.1016/j.cell.2020.09.020 |
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author | Yu, Chien-Hsiung Davidson, Sophia Harapas, Cassandra R. Hilton, James B. Mlodzianoski, Michael J. Laohamonthonkul, Pawat Louis, Cynthia Low, Ronnie Ren Jie Moecking, Jonas De Nardo, Dominic Balka, Katherine R. Calleja, Dale J. Moghaddas, Fiona Ni, Erya McLean, Catriona A. Samson, Andre L. Tyebji, Shiraz Tonkin, Christopher J. Bye, Christopher R. Turner, Bradley J. Pepin, Genevieve Gantier, Michael P. Rogers, Kelly L. McArthur, Kate Crouch, Peter J. Masters, Seth L. |
author_facet | Yu, Chien-Hsiung Davidson, Sophia Harapas, Cassandra R. Hilton, James B. Mlodzianoski, Michael J. Laohamonthonkul, Pawat Louis, Cynthia Low, Ronnie Ren Jie Moecking, Jonas De Nardo, Dominic Balka, Katherine R. Calleja, Dale J. Moghaddas, Fiona Ni, Erya McLean, Catriona A. Samson, Andre L. Tyebji, Shiraz Tonkin, Christopher J. Bye, Christopher R. Turner, Bradley J. Pepin, Genevieve Gantier, Michael P. Rogers, Kelly L. McArthur, Kate Crouch, Peter J. Masters, Seth L. |
author_sort | Yu, Chien-Hsiung |
collection | PubMed |
description | Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS. |
format | Online Article Text |
id | pubmed-7599077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-75990772020-11-05 TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS Yu, Chien-Hsiung Davidson, Sophia Harapas, Cassandra R. Hilton, James B. Mlodzianoski, Michael J. Laohamonthonkul, Pawat Louis, Cynthia Low, Ronnie Ren Jie Moecking, Jonas De Nardo, Dominic Balka, Katherine R. Calleja, Dale J. Moghaddas, Fiona Ni, Erya McLean, Catriona A. Samson, Andre L. Tyebji, Shiraz Tonkin, Christopher J. Bye, Christopher R. Turner, Bradley J. Pepin, Genevieve Gantier, Michael P. Rogers, Kelly L. McArthur, Kate Crouch, Peter J. Masters, Seth L. Cell Article Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS. Cell Press 2020-10-29 /pmc/articles/PMC7599077/ /pubmed/33031745 http://dx.doi.org/10.1016/j.cell.2020.09.020 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yu, Chien-Hsiung Davidson, Sophia Harapas, Cassandra R. Hilton, James B. Mlodzianoski, Michael J. Laohamonthonkul, Pawat Louis, Cynthia Low, Ronnie Ren Jie Moecking, Jonas De Nardo, Dominic Balka, Katherine R. Calleja, Dale J. Moghaddas, Fiona Ni, Erya McLean, Catriona A. Samson, Andre L. Tyebji, Shiraz Tonkin, Christopher J. Bye, Christopher R. Turner, Bradley J. Pepin, Genevieve Gantier, Michael P. Rogers, Kelly L. McArthur, Kate Crouch, Peter J. Masters, Seth L. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS |
title | TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS |
title_full | TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS |
title_fullStr | TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS |
title_full_unstemmed | TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS |
title_short | TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS |
title_sort | tdp-43 triggers mitochondrial dna release via mptp to activate cgas/sting in als |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599077/ https://www.ncbi.nlm.nih.gov/pubmed/33031745 http://dx.doi.org/10.1016/j.cell.2020.09.020 |
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