Motor neuron disease (MND) is a progressive condition that occurs when certain nerve cells degenerate and die. There are two types of motor neuron cells. The upper motor neuron begins in the brain and ends in the spinal cord. The lower motor neuron starts in the spinal cord and ends in the muscles. Now researchers from Melbourne are working to develop a potential treatment to slow the progression of MND, by taking the “sting” out of it, literally. By blocking an immune sensor called STING, the researchers were able to prevent inflammation from MND patient cells in mouse models. Their findings may open a new door of drug development for those with MND and neurodegenerative disorders.

Their findings, “TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS,” is published in Cell and led by Walter and Eliza Hall Institute researchers, Seth Masters, associate professor, and Alan Yu, with colleagues from the University of Melbourne and Hudson Institute.

Most people suffering from MND have an accumulation of a protein called TDP-43 within cells of the central nervous system. At least 60 mutations in the TARDBP gene have been linked to amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most mutations change amino acids in the TDP-43. Changes to the TDP-43 protein cause the protein to misfold and form protein clumps, which have been found in nerve cells that control motor neurons in some people with ALS.

The researchers investigated how the disease-causing inflammation is triggered in MND, said Masters. “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 team then used new inhibitors to block different components of this inflammatory pathway. Using cells from patients with MND, the researchers showed that blocking STING dramatically prevented inflammation and kept the cells alive longer.

Stimulator of interferon genes (STING) is a signaling molecule associated with the endoplasmic reticulum (ER) and is essential for controlling the transcription of numerous host defense genes, including type I interferons (IFNs) and pro-inflammatory cytokines.

The researchers are now looking forward to validating 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,” Masters said.

“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.”

The researchers are hopeful that their treatment could lead to more understanding and new treatments.

“We are hopeful this research could lead to a treatment for people with established MND, who currently have very few treatment options and a life expectancy post-diagnosis of just two to five years,” Masters added. “While it isn’t a cure, we hope it might extend life expectancy and dramatically improve the quality of life for people diagnosed with MND.”

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