TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

By Chien-Hsiung Yu, Sophia Davidson, C. Harapas, J. B. Hilton, Michael J. Mlodzianoski, P. Laohamonthonkul, Cynthia Louis, R. R. J. Low, Jonas Moecking, D. De Nardo and 16 more. Cell, 2020

850 citations recorded by the source corpus.

Summary 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.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/77ba9ac938c4f2db9ba55ff50b384be4c1b67021

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Citations in the corpus

• Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “Chromatin reader bromodomain-containing protein 4,487 P53P21 axis, and NFκB signaling pathway488 regulate immune surveillance by regulating the expression and type of SASP.”
• Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances (2025, neutral): “127 Intrigu-ingly, the voltage-dependent anion channel (VDAC) is a channel in the outer mitochondrial membrane.”
• Role of neuroinflammation in neurodegeneration development (2023, background): “TDP-43 aggregates can also mislocate into mitochondria and cause mtDNA release, leading to STING dependent upregulation of inflammatory cytokines.(81) Together, cGAS-STING activation occurs in response to a wide array of stimulus and generates multiple affection to the cell, including interferon res”
• Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “149,150 Indeed, the inhibition of mPTP opening with CsA reduced the cytosolic pools of mtDNA by 30% – 40%, and VDAC oligomerization inhibition with VBIT-4 reduced cytosolic mtDNA by 50 – 60%.”