‘Sting’ protein response to clean up damaged brain cells may accelerate progression of Parkinson’s disease

In studies of mice and human tissue, as well as live mice, Johns Hopkins Medicine researchers report that a problem in the normal process of cleaning up broken DNA in brain cells can accelerate the progression of Parkinson disease. Specifically, the researchers discovered that a protein called “STING” responds to cleaning signals in brain cells damaged by Parkinson’s disease by creating a cycle of inflammation that can accelerate disease progression.

The conclusions, published on April 4 in the Proceedings of the National Academies of Sciencescould advance the search for drugs and new drug targets to stop or slow the progression of Parkinson’s disease.

Parkinson’s disease is a neurodegenerative disease characterized by the accumulation of a misfolded protein, called alpha-synuclein, in brain cells. As misshapen proteins clump together, they kill brain cells called dopaminergic neurons, leaving behind vast swaths of dead brain matter. When these brain cells die, they impair a person’s ability to move, think, or regulate their emotions. Previous studies have shown that when brain cells are damaged by clumps of alpha-synuclein, they release pieces of damaged DNA into the nerve cell body.

Free-floating DNA is not good for neurons, so the immune system has developed ways to eliminate it.”

Ted Dawson, MD, Ph.D., director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at Johns Hopkins University School of Medicine

As part of this immune response, the STING – protein; STING stands for interferon-gene stimulator; triggers a cascade of inflammatory chemical signals that bring immune cells to the site to clean up damaged DNA. While this response may be beneficial in destroying viruses and bacteria in the rest of the body, researchers suspect that such an inflammatory response in the brain may upset the delicate balance of brain cell signals, leading to worsening disease. of Parkinson’s.

To investigate this possibility, the researchers began scanning lab-grown mouse brain cells exposed to misfolded alpha-synuclein aggregation for the presence of the STING protein. The Johns Hopkins team found that the highest levels of STING were present among brain support cells called microglia, which act as waste collectors in the brain. The presence of the STING protein in microglia suggests that microglia itself is susceptible to DNA damage in Parkinson’s disease. “When cleanup crew members themselves can malfunction, it poses a problem for the immune response in the brain,” Dawson says.

The researchers suspected that the inflammatory response initiated by STING could accelerate the immune response of microglia due to internal DNA damage. The response, the researchers suggest, may prompt microglia to unnecessarily destroy more dopamine neurons.

By examining the brain tissue of mice injected with misfolded alpha-synuclein, the researchers found that mice with deactivated STING proteins had less microglial activity and brain cell death. These mice also performed better in physical strength and movement tasks used to examine the progression of Parkinson’s disease in mice.

“By turning off 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 says.

The Johns Hopkins team also looked at the brain tissue of people who had died of Parkinson’s disease and found high levels of STING in their brain tissue.

Dawson’s research team plans to examine the STING cell signaling pathway for potential drug targets that could shut down the inflammatory response.

Other researchers involved in this study include Jared Hinkle, Jaimin Patel, Nikhil Panicker, Senthilkumar Karuppagounder, Devanik Biswas, Bonn Belingon, Rong Chen, Saurav Brahmachari, Olga Pletnikova, Juan Troncoso and Valina Dawson of Johns Hopkins.

This research was supported by the JPB Foundation, the Farmer Family Foundation, the Leonard and Madlyn Abramson Chair in Neurodegenerative Diseases, the National Institute for General Medical Studies of the National Institutes of Health (T32 GM136577), the National Institute on Aging (F30AG067643, K99AG066862) and Maryland Stem Cell Research Fund.

Source:

Journal reference:

Hinkle, J.T. et al. (2022) STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2118819119.

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