Study: Psychiatric challenges in young girls with autism are linked to larger amygdala
It was in 2016 that the present team of researchers first found a higher rate of growth in stem cells found in the brains of people with macrocephalic ASD compared to those derived from healthy individuals. Stem cells are the source of more specialized or differentiated cells and tissues in the body, including nerve cells. The increased growth rate could be part of the reason for the macrocephaly, or abnormally large head size, in this group of people – the researchers found that the stem cells were multiplying excessively during the period of brain development. The study
In the present study, they delved deeper into these stem cells found in the brain, also called neural precursor cells (NPCs). Their aim was to see if the abnormally high rate of proliferation caused more errors to occur and pile up during DNA replication. They used skin cells collected from people with ASD and macrocephaly, and from people without ASD. They then reprogrammed the cell’s biological clock to induce it to turn back into a stem cell that could give rise to nerve cells – the NPC.
These cells were now treated with a chemical that stimulates cell replication, and thus puts stress on the DNA replication. They first used stem cells from the non-ASD group to identify the most vulnerable segments of DNA, where the most damage was likely to build up. They then repeated the process with autistic individuals. The findings
The findings were remarkable. There were 36 genes that showed damage in NPCs obtained from people with ASD as well as from neurotypical (without ASD) individuals. However, NPCs from the first group showed much higher DNA damage levels. Secondly, 26/36 genes had already been found to be associated with ASD in other studies.
Study author Meiyan Wang says, “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.” The increased rate of proliferation of the NPCs is probably the reason for the macrocephaly as well as the replication stress that is a major cause of the ASD-linked mutations.
The researchers were able to detect the sites of DNA injury. However, it is not clear as to what fraction of this damage underwent repair before the subsequent differentiation of the cell, and how many cells differentiated into mature neurons carrying permanently altered DNA within their genome.
This will probably be the focus of future studies. Wang says, “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.” Journal reference:
Meiyan Wang, Pei-Chi Wei, Christina K. Lim, Iryna S. Gallina, Sara Marshall, Maria C. Marchetto, Frederick W. Alt, Fred H. Gage, Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability, Cell Stem Cell, https://doi.org/10.1016/j.stem.2019.12.013
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