Trisomy 21, the abnormal third copy of chromosome 21 causing developmental disorders in Down syndrome, has been shown to promote reorganization of the entire neural progenitor cell (NPC) genome, with the resulting gene transcription and cell function disruption being so similar to senescence that anti-senescence drugs could correct them in cell cultures.
Reported in the January 6, 2021, edition of Cell Stem Cell, these study findings suggest that senescence may be targeted for future Down syndrome treatment, said study leader Hiruy Meharena, a postdoctoral fellow in the Alana Down Syndrome Center at the Massachusetts Institute of Technology (MIT) at the time of the study.
"To our knowledge this is the first study to demonstrate that trisomy 21 induces similar genetic signatures to those seen in senescence and that anti-senescence drugs can alleviate the genetic, molecular and cellular signatures induced by trisomy 21," said Meharena, who is now an assistant professor of neurobiology and molecular biology at the University of California San Diego.
"There is a cell-type specific genome-wide disruption independent of the gene dosage response, which is a similar to that seen in senescence, suggesting that excessive senescence in the developing brain induced by the third copy of chromosome 21 could [explain] the neurodevelopmental abnormalities seen in Down syndrome," said Meharena.
"We observed that both induced pluripotent stem cells (iPSCs) and NPCs displayed a similar gene-dosage response, where approximately 25% of the expressed genes on chromosome 21 were deregulated; however, only NPCs displayed genome-wide transcriptional changes similar to the genome-wide changes observed in senescent cells," he told BioWorld Science.
"This study illustrates the importance of questioning the fundamental underlying mechanisms of neurological disorders," said senior author Li-Huei Tsai, professor of neuroscience and director of The Picower Institute for Learning and Memory at MIT.
In the new study, stem cells from volunteers were cultured to develop into NPCs, with the 3D chromosome architecture, several metrics of DNA structure and interaction, gene accessibility and transcription being compared in stem cells and NPCs.
The consequences of gene expression differences on important functions of these developmental cells were then studied, including their proliferation and migration in 3D brain tissue cultures.
Although stem cells were similar, NPCs were substantially affected by the third copy of chromosome 21, which caused chromosomal introversion, the main effects of which included more genetic interactions within each chromosome and fewer interactions among them.
"Genome-wide chromosomal introversion was observed by mapping the spatial chromatin organization using a chromosome conformation capture technique called Hi-C, which utilizes next-generation sequencing to identify genome-wide genetic interactions," explained Meharena.
"This observation is important, because for the first time we have shown that the upregulated genes are associated with the introverted regions of the genome, which are dislodged from the nuclear periphery where the inactive regions of the genome are localized."
These changes and differences in DNA conformation within the NPC nucleus were shown to lead to changes in gene transcription, causing important differences in cell function affecting development.
Although the significance of these genomic changes was not immediately apparent, this was subsequently shown to be similar to the genomic rearrangements and transcriptional alterations seen in senescent cells, prompting the MIT team to test whether senolytic drugs could undo these effects.
Two senolytics, dasatinib and quercetin, were shown to improve not only gene accessibility and transcription, but also cell migration and proliferation.
"We found that the combination of dasatinib and quercetin alleviated about 54% of the transcriptional disruption induced by trisomy 21, while rescuing the cell proliferation and migration deficits to similar levels observed in euploid NPCs," said Maharena.
However, due to significant side effects, these drugs are inappropriate for intervention in brain development in Down syndrome, necessitating a search for safer agents.
"Dasatinib is a kinase inhibitor used for treating various cancer types, but even at significantly lower concentrations than those used for cancer therapy, dasatinib's nonspecific nature may have off-target effects in both the mother and fetus," said Maharena.
"However, this senolytic combination may provide potential therapeutic intervention postnatally," he suggested.
Senescence and aneuploidy are known sources of cell stress, begging the question of whether this newly identified senescence-like character of Down syndrome NPCs is due to aneuploidy-induced stress and, if so, what that stress is.
Another implication concerns how excessive brain cell senescence might affect people with Down syndrome later in life.
For example, the risk of Alzheimer's disease is much higher at an earlier age in Down syndrome patients than in the general population, possibly because a key Alzheimer's risk gene is located on chromosome 21, so the newly identified tendency for senescence may also accelerate Alzheimer's development.
"Our study findings provide insight into the role of senescence in the brain morphogenesis abnormalities associated with numerous neurodevelopmental disorders that display brain structure deficits," said Maharena.
"Although senescence has predominantly been studied in aging-associated disorders, our findings for the first time indicate that senescence may play a major role in neurodevelopmental disorders with structural abnormalities."
Looking forward, he said, "our next endeavor will be to explore further the role of senescence in mouse models of Down syndrome and the efficacy of senolytic drugs in mice and other animal models."