In Down syndrome cells, genome-wide disruption mimics an aging-like state

Neural progenitor cells with a typical number of chromosomes showed significant outward migration during culture (top panel)

Additional chromosomes alter chromosomal conformation DNA accessibility to neural progenitors; research suggests aging as a potential target mechanism for future treatments

In Down syndrome, a third copy of chromosome 21 causes the 3D structure of the entire genome to reorganize in a key cell type in the developing brain, a new study shows

"There is a cell-type-specific genome-wide disruption that is not associated with a gene dose response

Li-hui Tsai and Hiruy Meharena consult images produced during the research in this 2019 photo

The study found that neural progenitor cells (NPCs), which develop into the main cells in the brain including neurons, are markedly characterized by aging, said Li-Huei Cai, senior author of the novel, but it was confirmed by the team's extensive work to elucidate the underlying mechanisms The effect of abnormal chromosome number, or aneuploidy, in the nucleus

"This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders," said Tsai, the Picower Professor of Neuroscience and director of the Alana Center, who is also the MIT Picauer Learning and Memory Director of the Institute

Genome-wide changes

Meharena and co-authors have spent years measuring differences between human cell cultures that differ only in whether they have a third copy of chromosome 21

In general the image that emerges in the npc is that the presence of the third copy causes all the other chromosomes to squeeze inward, like in a crowded elevator where one has to shrink one's position when one squeezes in

senescence

In the first few years of these data, the full significance of the genomic changes was not apparent, Meharena said, but then he read a paper showing very similar genomic rearrangements and transcriptional changes in senescent cells

After confirming that Down syndrome cells indeed had a similar signature of transcriptional differences, the team decided to test whether antiaging drugs could abolish this effect

The drugs have very significant side effects -- dasatinib is only given to cancer patients when other treatments aren't enough -- so they're not suitable for trying to interfere with brain development in people with Down syndrome, Meharena said

Aging is a stress response of cells

Another implication of the findings is that excessive aging of brain cells may affect people with Down syndrome later in life