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Stem Cell Defects Associated with Down Syndrome

Talan, Jamie

doi: 10.1097/01.NT.0000438145.37935.02
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Investigators reported that nerve stem cells from mice and from Down syndrome patients are less likely to grow and renew themselves with the extra dose of ubiquitin specific protease 16 (Usp16). Until now, no one has even considered Down syndrome as a stem cell disease.

Overexpression of a gene on chromosome 21 that regulates self-renewal could be responsible for some of the neurological deficits in adult patients with Down's syndrome, a team of researchers at Stanford University suggest.

Michael Clarke, MD, and postdoctoral scholar Maddalena Adorno, PhD, reported in the Sept. 19 issue of Nature that nerve stem cells from mice and from Down syndrome patients are less likely to grow and renew themselves with the extra dose of ubiquitin specific protease 16 (Usp16). Until now, no one has even considered Down syndrome as a stem cell disease.

“There appear to be defects in the stem cells in all the Down's syndrome tissues that we tested, including the brain,” said Dr. Clarke, associate director of Stanford's stem cell institute. “We believe that Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome.”

The Clarke lab studies the molecular regulation of stem cells. Too much self-renewal via stem cells can lead to cancer and too little can cause defects in the development and maintenance of organs and tissues. A decade ago, Dr. Clarke and his colleagues identified a molecule — Bmi-1 — that regulates self-renewal. They conducted a genetic screen and identified Usp16 as a molecule that removes a ubiquitin mark from histones on Bmi-1. They went on to show that Usp16 affects self-renewal, and that increased expression of Usp16 inhibited self-renewal. “It was clear that Usp16 plays a major role in stem cell defects,” Dr. Clarke said.

The gene is on chromosome 21. And that is precisely why they thought of looking at Down syndrome cells that almost always contain an extra (third) chromosome 21 and therefore an extra copy of Usp16. They compared differences in stem cell function in Down syndrome cells from two mouse models — one with three copies of 132 mouse genes corresponding to human chromosome 21, including Usp16 gene (Ts65Dn) and the other with three copies of 79 genes from the chromosome, but only two copies of Usp16 (Ts1Cje). The Ts65Dn mouse more closely mimics the human form of the disease with the craniofacial problems and learning and memory deficits.

Their laboratory experiments showed that the neural stem cells from the TS65Dn mice were less able to self-renew and grow normally than the cells culled from the Ts1Cje mice. In other studies, they reduced the expression of Usp16 in the cells from the T65Dn mice and these functional defects were corrected. Thus blocking Usp16 expression allowed the stem cell populations to self-renew. It was not a complete rescue, said Dr. Clarke. But they rescued 60 to 80 percent of the neural stem cell defects.

They also conducted studies on cells from skin and nerve progenitor cells from people with Down syndrome and found that the cells were much slower to grow. They reduced expression of Usp16 and the cells tended to grow normally.

Dr. Clarke said that the identification of stem cell defects in Down syndrome suggests that it could be a new target for treatment. Reducing the expression of Usp16 could help prevent some of the adult-onset memory problems common among Down syndrome patients.

The finding could also explain the observation that Down syndrome patients rarely develop solid tumors. If stem cells are inhibited then it would also limit the self-renewal of cancer cells, said Dr. Clarke. They are now looking to see if Usp16 protects against solid tumor growth. He said that the neural stem cell defects could also explain why people with Down's syndrome have smaller brains and cerebellar defects.

The scientists have also created a transgenic strain of the Ts65Dn mouse that has only two copies of Usp16. They showed that this normalized the expression of the Usp16 gene. They also looked at the neural progenitor cells, which were abnormal in the mouse with too much Usp16 expression. The neural progenitor cells from the new transgenic mice with two copies of Usp16 looked normal and were able to form neurospheres.

Dr. Clarke suspects that the stem cell defects could lead to an acceleration of the aging process, which could explain the early onset of Alzheimer's that occurs in more than half of all Down's syndrome patients.



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“Usp16 may contribute to Down syndrome, but it is not the whole story,” said Huntington Potter, PhD, professor of neurology and director of the Alzheimer's disease programs at the University of Colorado and a member of the Linda Crnic Institute for Down Syndrome. Other genes, including amyloid precursor protein, are also involved in regulating the cell cycle, noted Dr. Potter, who was not involved in the study.

“It [the study] is definitely intriguing,” said Dr. Potter. “They found one mechanism, but it is probably not the only one. The data could all be necessary but not sufficient to explain all of the defects in Down syndrome.”

If the Usp16 triplication is a major contributor to the stem cell renewal defect, then it is possible to focus research attention on reducing the dose of the enzyme, he added. “It could potentially have a therapeutic benefit.”

Dr. Potter said that part of the problem with the paper is that the authors and the scientists who wrote an accompanying editorial suggest that this stem cell defect may lead to an accelerated aging process. “That is just not the case,” Dr. Potter added. “Today, Down syndrome patients live out almost full lives and they don't get atherosclerosis or solid tumors. The problem in Down's syndrome is not due to early aging.”

Norman Sharpless, MD, a professor of medicine and genetics at The Lineberger Comprehensive Cancer Center at the University of North Carolina School of Medicine, co-wrote an editorial with George P. Souroullas, PhD, in Nature about the stem cell finding in Down's syndrome. In a phone interview, he explained that there has been a debate in the Down syndrome literature on whether the disorder was related to progeria. Recent findings in Down syndrome have quieted the discussion, “but this breathes new life into that argument,” Dr. Sharpless said. Progeria is also marked by severe stem cell defects. He believes that Down syndrome fits the profile of an accelerated senescence in aging.

Whatever the ultimate mechanism, the University of North Carolina scientists added that the finding could have treatment implications. “Usp16 enzyme could be a target for treating some aspects of Down's syndrome. In this regard, however, it is important to temper any optimism, because even if selective Usp16 inhibitors were developed, clinical trials for age-related conditions in Down syndrome would probably be challenging. Nevertheless, in suggesting that Usp16 trisomy creates a congenital disruption of the PcG-regulated epigenetic state in somatic stem cells, the present work furthers our understanding of stem-cell homeostasis during aging.”





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•. Adorno M, Sikandar S, Mitra SS, et al. Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature 2013;501(7467):380–384.
    •. Souroullas GP, Sharpless NE. Stem cells: Down's syndrome link to ageing. Nature 2013;501(7467):325–326.
      •. Neurology Today archive on Down's syndrome:
        © 2013 American Academy of Neurology