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

Abstract

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.

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

“…Indirect evidence for this idea is supported by recent findings of transcriptional dysregulation in pathways involved in mitochondrial function and energy production in TDP-43-depleted motor neurons [17]. Moreover, TDP-43 has been shown to exert toxicity by entering mitochondria and specifically impairing OXPHOS complex I via the preferential binding of mitochondrially transcribed ND3/6 mRNAs and by inhibiting their translation to cause mitochondrial dysfunction and neuronal loss [107], as well as triggering mitochondrial DNA release and neuroinflammatory cGAS/STING activation [112]. Finally, recent work by Onesto et al showed that there is compensatory mitochondrial biogenesis, as evidenced by PGC1α upregulation, in dermal fibroblasts derived from patients with C9orf72-ALS [77].…”

The Complexity of the cGAS-STING Pathway in CNS Pathologies

“…Increased mRNA levels of Ccl5 and Cxcl10 was found to be cGAS dependent in both human and mouse striatal HD tissue further implicating the cGAS-STING pathway in driving the neuroinflammatory response in HD ( Sharma et al, 2020 ). A relationship between STING and TDP-43, a hallmark protein of ALS has recently been established with TDP-43 found to trigger mtDNA release into the cytoplasm, activating the cGAS-STING pathway ( Yu et al, 2020 ). Increased cGAS and cGAMP, the STING activating molecule produced by cGAS was detected in spinal cords and in the cortex of ALS mice overexpressing TDP-43 (Prp-TDP-43 Tg/+ ).…”

“…Increased cGAS and cGAMP, the STING activating molecule produced by cGAS was detected in spinal cords and in the cortex of ALS mice overexpressing TDP-43 (Prp-TDP-43 Tg/+ ). When STING was genetically deleted from these mice, the average lifespan increased by 40% and the mice exhibited improved rotarod performance compared to Prp-TDP-43 Tg/+ mice with intact STING ( Yu et al, 2020 ). Furthermore, elevated levels of the STING activator cGAMP were detected in spinal cord samples from ALS patients ( Yu et al, 2020 ).…”

“…When STING was genetically deleted from these mice, the average lifespan increased by 40% and the mice exhibited improved rotarod performance compared to Prp-TDP-43 Tg/+ mice with intact STING ( Yu et al, 2020 ). Furthermore, elevated levels of the STING activator cGAMP were detected in spinal cord samples from ALS patients ( Yu et al, 2020 ). Together these findings implicate the cGAS-STING pathway in driving the damaging inflammatory processes present in ALS.…”

Metabolic ROS Signaling: To Immunity and Beyond

“…The non-selective MPTP may be permissive to DNA transport [ 124 , 125 ]. Translocation of mitochondrial DNA via MPTP was recently suggested in experiments with TDP-43-mediated inflammation; however, this suggestion was based largely on an effect of MPTP inhibitor cyclosporine A that was applied at a dose ~10 times higher than a specific dose [ 126 ]. An effect on an alternative target, calcineurin was also not ruled out.…”