CIRM funded study links rapid brain growth in autism to DNA damage

Meiyan Wang and Dr. Rusty Gage at the Salk Institute.
Image Credit: Salk Institute

Autism spectrum disorder (ASD), is a developmental disorder that comes in broad ranges and primarily affects communication and behavior. Many people with ASD also have macrocephaly, or unusually large heads. Unfortunately, understanding the underlying causes of this disorder and development of potential treatments has been slow.

However, Dr. Rusty Gage and his team at the Salk Institute in San Diego have discovered a unique pattern of DNA damage in brain cells derived from individuals with macrocephalic (larger than normal head) ASD.

In a previous study, Dr. Gage and his team discovered that brain stem cells in people with macrocephalic ASD grew more quickly compared to normal individuals. Brain stem cells have the ability to turn into various kind of cell types in the brain such as neurons. This finding led them to the possibly that the rapid growth of brain stem cells in people with macrocephalic ASD could lead to larger than normal brains.

In the current study, they continue their work by looking more closely at neural precursor cells (NPC), a certain type of brain stem cell. The researchers collected skin cells from individuals with marcocephalic ASD and normal individuals and used stem-cell reprogramming to turn these cells back into NPCs.

Cells that will eventually become neurons (brain stem cells) derived from individuals with autism spectrum disorder, shown in the right panel, exhibit increased DNA damage (shown in the red stain), compared to those derived from healthy individuals (left panel).
Image Credit: Salk Institute

As NPCs replicate and mature, it is normal for their DNA to accumulate small errors, most of which are corrected and never do any harm. But the researchers discovered that the NPCs they derived from macrocephalic ASD individuals acquired significantly higher levels of DNA damage compared to those derived from normal individuals. Furthermore, they found that the DNA damage was clustered around various genes that have been linked to ASD in separate studies.

In a news release, Dr. Gage commented on the impact of DNA damage during the cell replication process.

“Division, or replication, is one of the most dangerous things that a cell can do. 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.”

In the same news release, graduate student Meiyan Wang and first author of this study elaborates on these results and the future direction of this work.

“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. 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.”

The full results of this study were published in Cell Stem Cell.

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