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Down syndrome due to faulty stem cell regulation?

neuronsDown syndrome as a stem cell disease? It sounds like an unlikely mash-up of two hot-button research topics. But a study from the laboratory of cancer stem cell biologist Michael Clarke, MD, published today in Nature suggests that some of the learning and memory problems suffered by people with Down syndrome could be due in part to defective regulation of nerve stem cells. Furthermore, one gene could be the primary culprit. As described in our press release:

The finding marks the first time Down syndrome has been linked to stem cells, and addresses some long-standing mysteries about the disorder. Although the gene, called Usp16, is unlikely to be the only contributor to the disease, the finding raises the possibility of an eventual therapy based on reducing its expression.

Most people know that people with Down syndrome have three, rather than the normal two, copies of chromosome 21. It's not clear, however, which of the hundreds of excess genes are involved in the learning disabilities and unique craniofacial structure that are the hallmarks of the condition.

Now Clarke and postdoctoral scholar Maddalena Adorno, PhD, have shown that nerve stem cells from mice and people with Down syndrome are less able to grow and renew themselves than their unaffected peers. Furthermore, lowering the expression of Usp16 to more normal levels restores the ability of the cells to grow normally. As Clarke, who is also the associate director of Stanford's stem cell institute, described in the release, "There appear to be defects in the stem cells in all the tissues that we tested, including the brain. We believe Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome."

The new study’s findings suggest answers to many long-standing mysteries about the condition, including why people with Down syndrome appear to age faster and exhibit early Alzheimer’s disease. More from the release:

"This study is the first to provide a possible explanation for these tendencies,” said [Craig Garner, PhD, the co-director of Stanford’s Center for Research and Treatment of Down Syndrome and study co-author]. The fact that people with Down syndrome have three copies of chromosome 21 and the Usp16 gene “accelerates the rate at which stem cells are used during early development, which likely exhausts stem cell pools and impairs tissue regeneration in adults with Down syndrome. As a result, their brains age faster and are susceptible to early onset neurodegenerative disorders.”

There's still lots to be learned about whether and how this finding could be applied to people with Down syndrome:

“We are really interested in learning how other genes in this chromosomal region may be affecting stem cell renewal,” said Clarke. “We also want to understand how much we’re able to rescue the neurological defect by normalizing the expression of Usp16 in this mouse model. How does this compare to what is happening in humans? We’re sure it plays some significant role.”

Previously: Progress on drug treatments for cognitive aspects of Down syndrome, Moving toward a Down syndrome drug and More on the debate over "curing" Down syndrome
Photo of neurons provided by the California Institute for Regenerative Medicine, taken in the lab of Xianmin Zeng, PhD, at the Buck Institute for Age Research

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