Targeting an aspect of Down syndrome

University of Michigan researchers have determined how a gene that is known to be defective in Down syndrome is regulated and how its dysregulation may lead to neurological defects, providing insights into potential therapeutic approaches to an aspect of the syndrome.

Normally, nerve cells called neurons undergo an intense period of extending and branching of neuronal protrusions around the time of birth. During this period, the neurons produce the proteins of the gene called Down syndrome cell-adhesion molecule, or Dscam, at high levels. After this phase, the growth and the levels of protein taper off.

However, in the brains of patients with Down syndrome, epilepsy and several other neurological disorders, the amount of Dscam remains high. The impact of the elevated Dscam amount on how neurons develop is unknown.

Bing Ye, a faculty member at U-M’s Life Sciences Institute, found that in the fruit fly Drosophila, the amount of Dscam proteins in a neuron determines the size to which a neuron extends its protrusions before it forms connections with other nerve cells. An overproduction of Dscam proteins leads to abnormally large neuronal protrusions.

Ye also identified two molecular pathways that converge to regulate the abundance of Dscam. One, dual leucine zipper kinase (DLK), which is involved in nerve regeneration, promotes the synthesis of Dscam proteins. Another, fragile X mental retardation protein (FMRP), which causes fragile X syndrome when defective, represses Dscam protein synthesis. Because humans share these genes with Drosophila, the DLK-FMRP-Dscam relationship presents a possible target for therapeutic intervention, Ye said.

Many genes are involved in neurological disorders like Down syndrome, and how molecular defects cause the disease is complex.

"But because of the important roles of Dscam in the development of neurons, its related defect is very likely to be an aspect of Down syndrome and it may be an aspect of the syndrome that can be treated," said Ye, an assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.

Ye’s next step is to test the effects of overexpression of Dscam in mice to see how it changes the development of the nervous system and the behavior of the animal.

Down syndrome occurs in about one in 830 newborns; an estimated 250,000 people in the U.S. have the condition, according to the National Library of Medicine’s Genetics Home Reference.

Unraveling the molecular roots of Down syndrome

Researchers discover that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.

What is it about the extra chromosome inherited in Down syndrome—chromosome 21—that alters brain and body development? Researchers have new evidence that points to a protein called sorting nexin 27, or SNX27. SNX27 production is inhibited by a molecule encoded on chromosome 21. The study, published March 24 in Nature Medicine, shows that SNX27 is reduced in human Down syndrome brains. The extra copy of chromosome 21 means a person with Down syndrome produces less SNX27 protein, which in turn disrupts brain function. What’s more, the researchers showed that restoring SNX27 in Down syndrome mice improves cognitive function and behavior.

“In the brain, SNX27 keeps certain receptors on the cell surface—receptors that are necessary for neurons to fire properly,” said Huaxi Xu, Ph.D., Sanford-Burnham professor and senior author of the study. “So, in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects.”

SNX27’s role in brain function

Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly. With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.

SNX27 levels are low in Down syndrome

Then the team got thinking about Down syndrome. The SNX27-deficient mice shared some characteristics with Down syndrome, so they took a look at human brains with the condition. This confirmed the clinical significance of their laboratory findings—humans with Down syndrome have significantly lower levels of SNX27.

Next, Xu and colleagues wondered how Down syndrome and low SNX27 are connected—could the extra chromosome 21 encode something that affects SNX27 levels? They suspected microRNAs, small pieces of genetic material that don’t code for protein, but instead influence the production of other genes. It turns out that chromosome 21 encodes one particular microRNA called miR-155. In human Down syndrome brains, the increase in miR-155 levels correlates almost perfectly with the decrease in SNX27.

Xu and his team concluded that, due to the extra chromosome 21 copy, the brains of people with Down syndrome produce extra miR-155, which by indirect means decreases SNX27 levels, in turn decreasing surface glutamate receptors. Through this mechanism, learning, memory, and behavior are impaired.

Restoring SNX27 function rescues Down syndrome mice

If people with Down syndrome simply have too much miR-155 or not enough SNX27, could that be fixed? The team explored this possibility. They used a noninfectious virus as a delivery vehicle to introduce new human SNX27 in the brains of Down syndrome mice.

“Everything goes back to normal after SNX27 treatment. It’s amazing—first we see the glutamate receptors come back, then memory deficit is repaired in our Down syndrome mice,” said Xin Wang, a graduate student in Xu’s lab and first author of the study. “Gene therapy of this sort hasn’t really panned out in humans, however. So we’re now screening small molecules to look for some that might increase SNX27 production or function in the brain.”

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.

Extra chromosome 21 removed from Down syndrome cell line

University of Washington scientists have succeeded in removing the extra copy of chromosome 21 in cell cultures derived from a person with Down syndrome, a condition in which the body’s cells contain three copies of chromosome 21 rather than the usual pair.

A triplicate of any chromosome is a serious genetic abnormality called a trisomy. Trisomies account for almost one-quarter of pregnancy loss from spontaneous miscarriages, according to the research team. Besides Down syndrome (trisomy 21), some other human trisomies are extra Y or X chromosomes, and Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13), both of which have extremely high newborn fatality rates.

In their report appearing in the Nov. 2 edition of Cell Stem Cell, a team led by Dr. Li B. Li of the UW Department of Medicine described how they corrected trisomy 21 in human cell lines they grew in the lab.  The senior scientists on the project were gene therapy researchers Dr. David W. Russell, professor of medicine and biochemistry, and Dr. Thalia Papayannopoulou, professor of medicine.

The targeted removal of a human trisomy, they noted, could have both clinical and research applications.

Fragile X and Down Syndromes Share Signalling Pathway for Intellectual Disability

"We have shown for the first time that some of the proteins altered in Fragile X and Down syndromes are common molecular triggers of intellectual disability in both disorders," said Kyung-Tai Min, one of the lead authors of the study and a professor at Indiana University and the Ulsan National Institute of Science and Technology in Korea. "Specifically, two proteins interact with each other in a way that limits the formation of spines or protrusions on the surface of dendrites." He added: "These outgrowths of the cell are essential for the formation of new contacts with other nerve cells and for the successful transmission of nerve signals. When the spines are impaired, information transfer is impeded and mental retardation takes hold."