Researchers at the Salk Institute in La Jolla have discovered a unique pattern of DNA damage that arises in brain cells derived from individuals with a macrocephalic form of autism.
The observation, published last week in the journal Cell Stem Cell, helps explain what might go wrong in the brain during cell division and development to cause autism spectrum disorder.
“Division, or replication, is one of the most dangerous things that a cell can do,” said Salk Professor Rusty Gage, the study’s senior author and president of the Institute. “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.”
Autism, a developmental disorder of communication and behavior, affects about 1 in 59 children in the United States, according to the Centers for Disease Control and Prevention. Research into the underlying causes of the disorder, as well as possible treatments, has been slow.
In 2016, Gage and his colleagues discovered that brain stem cells from people with the macrocephalic form of autism grew more quickly than cells from unaffected individuals. Brain stem cells are precursors to more-specialized types of cells, such as neurons.
The finding explained, in part, why many people with autism also have macrocephaly, or unusually large heads. A greater proliferation of brain stem cells during development can lead to larger brains.
In the new research, Gage and his colleagues again looked at these neural precursor cells. As all cell types proliferate and mature during embryonic development, it’s normal for their quickly-replicating strands of DNA to accumulate small errors, most of which are corrected and never do any harm. The researchers wondered whether this DNA damage that occurred during the stress of replication was more common in the quickly-dividing neural precursors of people with autism.
The researchers collected skin cells from individuals with both autism and macrocephaly, as well as from normal individuals, and used stem-cell reprogramming technology to coax each person’s cells into neural precursor cells.
Gage’s team then used a chemical compound to induce replication stress and studied where DNA damage was most likely to accumulate. They compared this induced damage in cells from individuals without autism to where DNA damage naturally accumulated in the cells from people with autism.
The cells from autistic individuals had heightened levels of DNA damage, 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.
“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,” said Meiyan Wang, a graduate student in the Gage lab and first author of the new paper.
That damage could be one source of mutations associated with autism, through further research is necessary to understand how it affects neuronal function in the long term.
The Salk Institute is an independent, nonprofit research organization and its building is an architectural landmark.
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