Accumulation of a protein known as TDP-43 is a hallmark of disease in almost all patients with amytrophic lateral sclerosis, and many individuals with frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, or diffuse Lewy body disease. TDP-43-associated neurodegeneration in general has been linked to inflammation, and interestingly, these inflammatory signals precede symptoms of disease. This suggests that inflammation contributes to disease pathogenesis, rather than simply acting as a marker of disease. We have now identified the primary innate immune pathway in cells that triggers neuroinflammation due to TDP-43. Unexpectedly this is driven by an innate immune pathway which is an immune sensor that recognises stray DNA in the cytoplasm of cells, cGAS/Sting.
TDP-43 releases mitochondrial DNA to activate cGAS/Sting
Normally, DNA remains within the nucleus or mitochondria of cells, but if stray DNA gets into the cytoplasm it can be recognised by cGAS/Sting, leading to inflammation. Indeed, it was already known that TDP-43 can get into mitochondria, and we found that this is what causes mitochondrial DNA to leak into the cytoplasm and trigger inflammation.
Pharmacologic inhibition of cGAS/Sting protects prevents TDP-43 driven inflammation
Critically, we have obtained a small molecule inhibitor of Sting (H-151), and found that it can block neuroinflammation triggered by TDP-43 for cell lines in vitro. H-151 is being commercialised by the company IFM therapeutics (Boston), who have agreed to support our project, looking towards first in man clinical trials.
Therefore, in summary, we suggest that patients with accumulation of TDP-43 suffer from neuroinflammation caused by the cGAS/Sting pathway. This occurs because TDP-43 destabilises mitochondria and the DNA leaks into the cytoplasm, activating cGAS/Sting. We propose to inhibit Sting and thus treat a mouse model of ALS caused by TDP-43, and confirm our results in primary human cells, as important steps towards getting this therapy into the clinic.