Toxic clumps due to the buildup of the TDP-43 protein can trigger the neuronal inflammation that precedes symptoms of amyotrophic lateral sclerosis (ALS) by activating an inflammatory signaling pathway called cGAS-STING, a study reported.
Its findings suggest that targeting this inflammatory signaling may be an effective way of treating ALS.
The study, “TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS,” was published in Cell.
The binding protein TDP-43 is believed to play a central role in ALS development. Normally, this protein is located in the nucleus of brain cells, the cellular compartment that contains a cell’s DNA. But in ALS, clumps of TDP-43 form outside of the nucleus, which are thought to be toxic.
Another feature of ALS is increased inflammation in the brain, particularly, but also in the spinal cord. In mouse models, such inflammation is seen to occur before the onset of overt symptoms — suggesting that inflammation is a cause of ALS, rather than an incidental disease marker.
Researchers at the Walter and Eliza Hall Institute, in Australia, identified a molecular system by which TDP-43 accumulation triggers brain inflammation, demonstrating a direct biochemical connection between these two features of ALS.
First, using cells in dishes, the researchers found that a mutated TDP-43 could not trigger inflammation if cells had been genetically engineered to lack the protein cyclic GMP-AMP synthase, or simply cGAS.
cGAS is known to work by activating another protein, called stimulator of interferon genes (STING), which is a well-established driver of inflammation. Consistently, TDP-43 did not trigger inflammation in cells lacking STING. Treating cells with compounds that block (inhibit) STING also prevented the inflammation caused by TDP-43 clumping.
“Using cells from patients with MND [motor neuron disease, a group of disorders that includes ALS] that we can turn into motor neurons in a dish, we showed that blocking STING dramatically prevented inflammation and kept the cells alive longer,” Seth Masters, PhD, an associate professor at the institute and study co-author, said in a press release. “This is an exciting first step before taking these inhibitors into the clinic for treatment for MND.”
These findings were also replicated in a mouse model of ALS. In animals engineered to lack STING, disease progression was slowed by 58%, and their median lifespan increased by 40%. Mice engineered to produce lower levels of STING also had slower disease progression and longer lifespans, though to a lesser degree.
Treating mice with a STING inhibitor once their disease started resulted in lesser inflammation and fewer neurons being lost.
“This administration regimen of a STING inhibitor at disease initiation provides hope that early intervention in patients could also provide a significant delay in neurodegeneration and highlights the translational potential of targeting this pathway in ALS,” the researchers wrote.
Disease onset, or the start of its symptoms, however, was not affected by STING inhibition.
“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,” Masters said.
Within cells, the cGAS-STING pathway normally gets activated by DNA in the cytosol, the fluid part of the cell’s cytoplasm. This is important for activating an immune response to some viruses and bacteria; cGAS-STING can sense an infectious agent’s DNA and trigger inflammation to fight the infection.
Although most of a cell’s DNA is housed in its nucleus, some DNA is also found in mitochondria, the powerhouse of cells. Researchers determined, via a series of molecular experiments, that TDP-43 causes mitochondrial DNA (mtDNA) to leak into the cytosol, triggering the activation of the cGAS-STING pathway.
Further experiments also identified some of the specific mitochondrial proteins involved in the TDP-43-mediated release of mtDNA.
Evidence of increased cGAS-STING activity in spinal cord samples from ALS patients, compared with samples from people with multiple sclerosis, another neurodegenerative disorder, was also found.
“This work identifies a novel mechanism by which neuroinflammation [brain, spinal cord inflammation] is triggered in TDP-43 [protein-driven diseases],” the researchers concluded. “Our assessment of cells lines, a mutant TDP-43 mouse model, and human ALS-affected spinal cord samples provides support for a model where TDP-43 liberates mtDNA into the cytoplasm.”
Their study, by identifying this pathway and suggesting its role in the disease, may pave the way for future treatments.
“We are hoping to develop a new class of drugs that would act as STING inhibitors to stop the progression of neurodegenerative disorders, such as MND, frontotemporal dementia and Parkinson’s disease,” Masters said.
“While it isn’t a cure, we hope it might extend life expectancy and dramatically improve the quality of life” for these people, he added.
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