The research team has uncovered how inflammation in MND is triggered. Pinpointing the molecules involved in this pathway could be a first step towards a new treatment for MND.
They found that by blocking an immune sensor called STING, they could dramatically prevent inflammation from MND patient cells, paving the way for a new class of drugs to be developed for people with neurodegenerative disorders, such as MND. The discovery was published in the journal Cell.
Most people suffering from 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 researchers investigated how the disease-causing inflammation is triggered in MND, said the author. "This unexpectedly identified that an immune sensor called STING is activated downstream of TDP-43. Fortuitously, our team had already studied the role of STING in other inflammatory diseases and are now working out how to block it."
The authos showed that the 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.
"Using cells from patients with MND that we can turn into motor neurons in a dish, we showed that blocking STING dramatically prevented inflammation and kept the cells alive longer. This is an exciting first step before taking these inhibitors into the clinic for treatment for MND.
The author said the research had also established activation of STING in people who had passed away due to MND.
"We are now aiming to validate a biomarker of the pathway earlier in the disease progression. Once this neuroinflammatory biomarker is validated, we will better understand which patients will benefit the most from treatments targeting the pathway," the author said.
"With this knowledge, there is the potential to develop a treatment for patients with MND.
"Interestingly, our preclinical models suggest that although the anti-inflammatory drugs that inhibit STING did not prevent disease onset, they did slow the degenerative progression of disease."
https://www.cell.com/cell/fulltext/S0092-8674(20)31161-2
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ftdp-43-triggers&filter=22
STINGing the ALS
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