articleCellOct 1, 2020NLHYBRID OA

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

CYChien‐Hsiung YuSDSophia DavidsonCRCassandra R. HarapasJBJames B. HiltonMJMichael J. Mlodzianoski

The University of Melbourne · Walter and Eliza Hall Institute of Medical Research · +9 more institutions

PubMed
Indexed incrossrefpubmed

Abstract

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…

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974
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Topics & keywords

Topics
Keywords
  • Biology
  • Downregulation and upregulation
  • Cell biology
  • Mitochondrion
  • Mitochondrial DNA
  • Amyotrophic lateral sclerosis
  • Neurodegeneration
  • Signal transduction
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