DNA damage in brain cells may explain some forms of autism, study says

Jan. 30 (UPI) -- Researchers believe they have identified a pattern of DNA damage that occurs during brain cell division and development and, potentially causes autism.

In findings published Thursday in Cell Stem Cell, scientists from the Salk Institute in La Jolla, Calif., and colleagues observed the pattern in brain cells derived from individuals with a macrocephalic form of autism spectrum disorder, or ASD.

People with macrocephalic ASD typically have abnormally large heads.

"Division, or replication, is one of the most dangerous things that a cell can do," study co-author Rusty Gage, president of the Salk Institute, said in a press release. "Most DNA damage is repaired through a remarkably efficient repair process, but errors occur when the rate of division is altered genetically or environmentally, which can lead to long term functional defects."

ASD is a developmental disorder that affects approximate one in 59 children in the United States, according to the Centers for Disease Control and Prevention. Its exact cause remains unknown.

In 2016, Gage and his colleagues discovered that brain stem cells collected from people with macrocephalic ASD grew more quickly than cells from those who did not have the condition. According to Gage, the finding explained, at least in part, why many people with ASD also have macrocephaly.

In the most recent study, the team analyzed these neural precursor cells, or NPCs, to learn whether DNA damage that occurs during the stress of replication was more common in people with autism. It's common for fast-replicating strands of DNA to accumulate small errors as cells proliferate and mature during embryonic development -- or as a fetus matures in utero.

Most of these errors are corrected during development and never do any harm.

The researchers collected skin cells from individuals with both ASD and macrocephaly, as well as from individuals without ASD, and used stem-cell reprogramming technology to coax each person's cells into NPCs. A chemical compound was then used to induce replication stress on the NPCs derived from people without autism and studied where DNA damage was most likely to accumulate.

When researches compared this induced damage in cells to naturally accumulated damage in cells from people with autism, they found the NPCs from autistic individuals had heightened levels of DNA damage.

The damage, they report, was clustered in 36 of the same genes that had also been damaged in healthy cells exposed to replication stress. And 20 of the genes had been previously linked to autism in separate genetic studies.

Based on their findings, the researchers believe that fast proliferation of NPCs may lead to both macrocephaly and cellular stress that spurs DNA damage -- which could be one source of mutations associated with ASD.

While the technology used in the study told the researchers where DNA damage occurred, they don't know how much of that damage was repaired before cells matured into adult neurons and how much of it leads to lasting mutations.

"What the new results are telling us is that cells from people with macrocephalic autism not only proliferate more but naturally experience more replication stress," explained co-author Meiyan Wang, a graduate student in the Gage lab at Salk. "We'd like to look deeper at how replication stress and DNA damage affects neuronal function in the long term and whether adult neurons arising from these stem cells have more mutations than usual."