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Accumulated DNA damage linked to neurodegeneration in a rare pediatric disorder

St. Jude Children’s Research Hospital scientists have identified the disease process that underlies Aicardi-Goutières syndrome, a debilitating illness with no known cure

Memphis, Tennessee, October 15, 2021

Five scientists sitting outside at a picnic table and talking about research.

From left: Research from Susanna Downing, Young Don Kwak, Ph.D., (standing), Aditi, Ph.D., (seated), Yang Li (standing) and Peter McKinnon, Ph.D., director of the Center for Pediatric Neurological Disease Research, found that defects in DNA repair cause the severe neurodevelopmental damage associated with Aicardi-Goutières syndrome, a rare pediatric neurological disease. (Picture reflects CDC guidelines at time of the photo)

Unrepaired DNA damage is primarily responsible for the devastating neurodevelopmental abnormalities associated with Aicardi-Goutières syndrome (AGS), a rare childhood disorder. The findings from St. Jude Children’s Research Hospital overturn the belief that neuroinflammation was to blame. The paper appeared today in Neuron.

Working in a newly developed mouse model of human AGS, St. Jude researchers showed that loss of the enzyme RNASEH2 led to genome instability in rapidly dividing cells of the developing brain. The unrepaired DNA damage and resulting loss of cells were the primary cause of the microcephaly, seizures and other brain abnormalities associated with AGS, the researchers reported.

“This study clarifies that defects in DNA repair cause severe neurodevelopmental damage in children affected by the disease,” said corresponding author Peter McKinnon, Ph.D., director of the St. Jude Center for Pediatric Neurological Disease Research.

The findings highlighted the importance of RNASEH2 in the developing nervous system. The work also provides insights for studies to better understand the disease process. There is no known cure for AGS and about 80% of children with the severe form die within the first decade of life.

Neurodegenerative process identified

The RNASEH2 gene is altered in more than half of AGS patients, making it the most common mutation. But the syndrome is also associated with neuroinflammation that stems from increased type 1 interferon signaling. Type 1 interferon is part of the inflammatory immune response.

“Prior to this work, researchers understood that the enzyme RNASEH2 had a role in repairing DNA damage, but AGS was considered a neuroinflammatory disease,” McKinnon said.

St. Jude researchers developed a mouse model of AGS to learn more about the disease process. Investigators showed that RNASEH2 played a critical role in maintaining DNA integrity. Mice that lacked RNASEH2 developed neurological damage that mirrored human AGS. In contrast, inhibiting type 1 interferon did not significantly reduce the defects.

“The enzyme removes ribonucleotides that are incorporated into, and damage, DNA in rapidly dividing cells in the developing nervous system,” McKinnon said. “Our data suggest that loss of RNASEH2 leaves DNA damage unrepaired, letting it accumulate and trigger neurodegeneration that is independent of neuroinflammation.”

RNASEH2 and ATM: An unexpected connection

Investigators also identified an unexpected connection between RNASEH2 and the enzyme ATM. Mutations in ATM cause ataxia telangiectasia, a rare neurodegenerative disorder.

Researchers showed that RNASEH2 and ATM as well as the protein p53 are in the same pathway and help to maintain genome integrity. Loss of RNASEH2 activates ATM to protect developing neurons from DNA damage. In this study, inactivation of both enzymes worsened DNA damage, neurodegeneration and neuroinflammation.

Pediatric Translational Neuroscience Initiative

The mouse model was key to identifying the AGS disease process and will aid efforts to understand the importance of genome stability in normal brain growth and development.

The research reflects the hospital’s commitment to understanding and treating children with neurological disorders. In 2020, St. Jude created the Pediatric Translational Neuroscience Initiative. The effort brings together laboratory and clinical research, local and international collaborations, and partnerships with drug companies to bring promising treatments to children with neurological diseases.

The Pediatric Translational Neuroscience Initiative is directed by J. Paul Taylor, M.D., Ph.D., and includes the Center for Pediatric Neurological Diseases Research, led by McKinnon. Richard Finkel, M.D., directs the clinical component, called the Center for Experimental Neurotherapeutics. Kristin Stephenson leads strategy and alliances for the initiative.

Authors and funding

Aditi, Ph.D., of St. Jude is the study’s first author. The other authors are Susanna Downing, Young Don Kwak and Yang Li of St. Jude; and Patrick Schreiner, Timothy Shaw and Helen Russell, formerly of St. Jude.

The research was funded by grants from the National Institutes of Health (NS37956, CA21765) and ALSAC, the fundraising and awareness organization of St. Jude.


St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food — because all a family should worry about is helping their child live. To learn more, visit or follow St. Jude on social media at @stjuderesearch.