The discovery, published in Cell on the 8th of October, was led by Walter and Eliza Hall Institute researchers Associate Professor Seth Masters and Dr Alan Yu, with colleagues from the University of Melbourne (Associate Professor Peter Crouch), the Hudson Institute for Medical Research (Dr Michael Gantier), and The Florey Institute of Neuroscience and Mental Health (Associate Professor Bradley Turner). The research was supported by MND Research Australia via the Superball XI MND Research Grant (Masters) and the Betty Laidlaw MND Research Grant (Crouch).
At a glance
- Researchers have uncovered a major immune pathway that is activated by a protein that accumulates in patients with MND
- By blocking the STING immune sensor, researchers were able to prevent inflammation from patient motor neurons, and thus promote motor neuron survival
- The discovery is a first step towards a treatment therapy for MND
Halting the inflammatory response
Most people with MND have an accumulation of a protein called TDP-43 within cells of the central nervous system. This build-up is associated with an inflammatory response that precedes major symptoms of MND.
The research team investigated how the disease-causing inflammation is triggered in MND. They unexpectedly identified that an immune sensor called STING is activated downstream of TDP-43. Fortuitously, their team had already studied the role of STING in other inflammatory diseases and had been working out how to block this pathway in disease
From this earlier research they were able to access new inhibitors – drug-like compounds – that could block different components of this inflammatory pathway.
They then showed that in in the mutant TDP-43 mouse model of MND, they could dramatically reduce MND disease progression by genetically deleting the STING pathway. Similarly, treatment of the mutant TDP-43 mice with STING inhibitors also reduced disease progression.
They also showed in neurons derived directly from MND patients (inducible pluripotent stem cells (iPSCs)), that these inhibitors could block inflammation and prevent the cells dying early.
It should be noted though that in these cell and animal-based studies targeting the STING pathway did not prevent disease onset but rather inhibited disease progression.
The researchers also showed that the STING pathway was activated in people who had died due to MND by looking in tissue samples from former patients. They are hoping that they might also be able to measure STING activation in patients as a “biomarker” to both follow disease development and also identify which patients would benefit best from treatments targeting this pathway.
The researchers are now hoping to further develop better inhibitors of the STING pathway that might one day be tested in humans.
The research was also funded by the Australian National Health and Medical Research Council, Veski, HHMI-Wellcome Trust, the Sylvia and Charles Viertel Foundation (SLM), the Australian Research Council, Fellowship Fonds de recherche du Québec-Santé, the WEHI Centenary Fellowship and Ormond College’s Thwaites Gutch Fellowship in Physiology, the Australian Phenomics Network, the Ian Potter Centre for Genomics and Personalized Medicine and the Victorian Government.
The full publication is available
here
Title: TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS