STING Protein Drives Inflammation and Neuronal Loss, Study Finds
A protein called STING, which normally helps sense infectious threats like viruses, may help to drive the inflammation that spurs neurodegeneration in Parkinson’s disease, according to a study in mouse and cell models.
The study, “STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy,” was published in Proceedings of the National Academy of Sciences.
Parkinson’s is characterized by the buildup of abnormal clumps of alpha-synuclein protein in the brain, which damages nerve cells or neurons. Previous research has shown that alpha-synuclein can cause damage to a cell’s DNA, resulting in pieces of DNA leaking from the cell nucleus — the compartment that houses DNA.
Under ordinary circumstances, DNA in a cell is only kept in the nucleus. As such, any DNA outside the nucleus signals that something is wrong. For example, viruses infect cells by injecting their genetic material, so DNA outside the nucleus can be a sign that a cell is infected with a virus.
“Freely floating DNA [outside the nucleus] is not good for neurons, so the immune system has evolved ways to clear it out,” Ted Dawson, MD, PhD, a neurology professor at Johns Hopkins University and study author, said in a press release.
The protein STING is a central part of the immune response to free-floating DNA. Its name is short for stimulator of interferon genes, referring to how STING’s activation drives the expression of powerful pro-inflammatory signaling molecules called interferons.
Theoretically, DNA damage due to alpha-synuclein accumulation could lead to free-floating DNA and STING activation. However, whether this protein contributes to diseases driven by alpha-synuclein had not been investigated.
Hopkins researchers conducted a series of experiments in cell and mouse models to learn more.
Initial cell work found that exposure to aggregated alpha-synuclein led to high levels of STING in microglia, the resident immune cells of the brain that also act as “trash collectors,” helping to clear away cellular debris. Since STING was expressed in the microglia themselves, it indicates that these cells may be susceptible to DNA damage driven by alpha-synuclein.
“When the cleanup crew members themselves may be malfunctioning, it poses a problem for the immune response in the brain,” Dawson said.
Experiments in mice given brain injections of alpha-synuclein further showed that the disease-driving protein led to STING activation in microglia.
Notably, when the researchers injected alpha-synuclein into the brains of STING-deficient mice, those lacking this protein, the mice had markedly lower microglial activation and less death of neurons than mice with functional STING.
“Remarkably, STING-deficient mice were protected from dopaminergic neuron loss in this model,” the researchers wrote.
“By deactivating STING, we could turn off the inflammatory response in mice, suggesting that this pathway is involved in the inflammation that occurs with pathological alpha-synuclein,” Dawson added.
The team also observed STING activation in brain tissue from people with Parkinson’s disease.
“Our results suggest that microglial STING activation contributes to both the neuroinflammation and neurodegeneration arising” from Parkinson’s, the researchers concluded.
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