"Cell Stem Cell" is a new breakthrough in changing the paradigm!

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

The study, published in Cell Stem Cell, establishes aging as a potential treatment Mechanisms of Down syndrome

"There is a deliberate genome disruption in one cell type, independent of the gene dose response," Meharena said.

Li-Huei Tsai, senior author of the study, said the finding that neural precursor cells (NPCs) have senescent features, a finding that develops into major cells in the brain, including neurons, is remarkable and novel , but the group's extensive work to elucidate the underlying mechanism of the effects of abnormal chromosome number, or rather, asphericity, within the nucleus

"This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders," said Professor Tsai

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

Overall, the image that emerges in NPCs 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 footing when one squeezes in point

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 do indeed have a similar signature of transcriptional differences, the team decided to test whether drugs that clear senescent cells could abolish this effect

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

Aging is a stress response of cells

One question raised by the new findings is whether the aging-like properties of Down syndrome NPCs are indeed the result of aneuploidy-induced stress, and if so, what exactly is stress

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

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Cell Stem Cell

Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors