Lymphatic disorder may cause stillbirth, chronic disease in affected children

In a breakthrough discovery, South Australian researchers have identified a genetic mutation responsible for a lymphatic disorder that may be responsible for causing stillbirth or severe, chronic disease in affected children.

The findings were published in the journal 'Science Translational Medicine'.

An anomaly in the development of lymphatic vessels in unborn children, leading to fluid accumulating in the heart, lungs, and other organs, was uncovered by the scientists from the Centre for Cancer Biology (CCB) based at the University of South Australia (UniSA) and SA Pathology.

CCB Director Professor Natasha Harvey said a genetic study of six families affected by stillbirth or lymphoedema revealed the link between a mutated protein-coding gene called MDFIC and fluid accumulation in vital organs and tissues.

This demonstrated that MFDIC is important for controlling the growth and development of the lymphatic vessels in the foetus for the first time.

"The lymphatic system is a network of vessels (pipes) and nodes (filters and control centres) important for maintaining fluid balance in our tissues and transporting infection-fighting white blood cells throughout our bodies," Prof Harvey said.

"We determined that MDFIC controls cell migration, an important early event during the formation of the lymphatic vessel valves. The genetic variants we have found in our study reveal a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature."

"If the lymphatic valves don't form properly, lymph fluid accumulates in critical organs such as the heart and lungs, causing major respiratory problems that may eventuate in stillbirth or chronic disease."

An SA Pathology research team headed by Professor Hamish Scott initially found the genetic link in an Australian family. Their international colleagues in Belgium, Germany, and the US reported variants in the same gene, MDFIC, in several patients with the same lymphatic disorder.

Prof Harvey said, the disorder, known as the central conducting lymphatic anomaly (CCLA), is one of a group of severe lymphatic disorders and may result in stillbirth, or severe chronic disease in affected children.

Few effective treatments are available but with continued identification of the genetic causes of CCLAs, Prof Harvey says the next step is to develop new therapeutic drugs to combat the disease.

"There are existing drugs that may be used to treat these disorders, but we need to make sure that the signalling pathway that's treated by those drugs is the same pathway that is affected in our patients.

"This project is about the power of collaboration at a local level, national level, and international level, so that's been really important. Science is done in teams and we have great research teams here in Adelaide at the Centre for Cancer Biology. Our Ph.D. students and postdoctoral fellows have been integral to this work. They have really driven it and we're delighted to be working with such a group of talented people."

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Neuroscientists Reveal How the Brain Selectively Remembers New Places

When you enter a room, your brain is bombarded with sensory information. If the room is a place you know well, most of this information is already stored in long-term memory. However, if the room is unfamiliar to you, your brain creates a new memory of it almost immediately.

MIT neuroscientists have now discovered how this occurs. A small region of the brainstem, known as the locus coeruleus, is activated in response to novel sensory stimuli, and this activity triggers the release of a flood of dopamine into a certain region of the hippocampus to store a memory of the new location.

“We have the remarkable ability to memorize some specific features of an experience in an entirely new environment, and such ability is crucial for our adaptation to the constantly changing world,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory.

“This study opens an exciting avenue of research into the circuit mechanism by which behaviorally relevant stimuli are specifically encoded into long-term memory, ensuring that important stimuli are stored preferentially over incidental ones,” adds Tonegawa, the senior author of the study.

Akiko Wagatsuma, a former MIT research scientist, is the lead author of the study. 

New places
In a study published about 15 years ago, Tonegawa’s lab found that a part of the hippocampus called the CA3 is responsible for forming memories of novel environments. They hypothesized that the CA3 receives a signal from another part of the brain when a novel place is encountered, stimulating memory formation.

They believed this signal to be carried by chemicals known as neuromodulators, which influence neuronal activity. The CA3 receives neuromodulators from both the locus coeruleus (LC) and a region called the ventral tegmental area (VTA), which is a key part of the brain’s reward circuitry. The researchers decided to focus on the LC because it has been shown to project to the CA3 extensively and to respond to novelty, among many other functions.

The LC responds to an array of sensory input, including visual information as well as sound and odor, then sends information on to other brain areas, including the CA3. To uncover the role of LC-CA3 communication, the researchers genetically engineered mice so that they could block the neuronal activity between those regions by shining light on neurons that form the connection.

To test the mice’s ability to form new memories, the researchers placed the mice in a large open space that they had never seen before. The next day, they placed them in the same space again. Mice whose LC-CA3 connections were not disrupted spent much less time exploring the space on the second day, because the environment was already familiar to them. However, when the researchers interfered with the LC-CA3 connection during the first exposure to the space, the mice explored the area on the second day just as much as they had on the first. This suggests that they were unable to form a memory of the new environment.

The LC appears to exert this effect by releasing the neuromodulator dopamine into the CA3 region, which was surprising because the LC is known to be a major source of norepinephrine to the hippocampus. The researchers believe that this influx of dopamine helps to boost CA3’s ability to strengthen synapses and form a memory of the new location.

They found that this mechanism was not required for other types of memory, such as memories of fearful events, but appears to be specific to memory of new environments. The connections between the LC and CA3 are necessary for long-term spatial memories to form in CA3.

“The selectivity of successful memory formation has long been a puzzle,” says Richard Morris, a professor of neuroscience at the University of Edinburgh, who was not involved in the research. 

“This study goes a long way toward identifying the brain mechanisms of this process. Activity in the pathway between the locus coeruleus and CA3 occurs most strongly during novelty, and it seems that activity fixes the representations of everyday experience, helping to register and retain what’s been happening and where we’ve been.”

Choosing to remember
This mechanism likely evolved as a way to help animals survive, allowing them to remember new environments without wasting brainpower on recording places that are already familiar, the researchers say.

“When we are exposed to sensory information, we unconsciously choose what to memorize. For an animal’s survival, certain things are necessary to be remembered, and other things, familiar things, probably can be forgotten,” Wagatsuma says.

Still unknown is how the LC recognizes that an environment is new. The researchers hypothesize that some part of the brain is able to compare new environments with stored memories or with expectations of the environment, but more studies are needed to explore how this might happen.

“That’s the next big question,” Tonegawa says. “Hopefully new technology will help to resolve that.”

The research was funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.
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New molecular mechanism can reverse genetic defect responsible for Friedreich's ataxia

Scientists at Tufts University have identified a molecular mechanism that could reverse the genetic defect responsible for Friedreich's ataxia, a neurodegenerative disease that leaves its victims with difficulty walking, a loss of sensation in the arms and legs and impaired speech caused by degeneration of nerve tissue in the spinal cord.

The researchers report today in the Proceedings of the National Academy of Sciences that the genetic anomaly that causes the disease -- the multiple repetition of a three letter DNA sequence -- could potentially be reversed by enhancing a natural process that contracts the repetitive sequences in living tissue.

Friedreich's ataxia is a genetic disease caused by the presence of an expanded repetition of a three letter genetic sequence, GAA in the FXN gene, which encodes for frataxin, a protein required for proper function of the mitochondria -- the cell's "batteries" that generate the fuel to keep all other cell functions running.

Healthy people usually have 8 to 34 GAA repeats, carriers have 35 to 70 repeats, and individuals that exhibit disease symptoms have more than 70 -- and commonly have hundreds of repeats.

With more DNA repeats, it becomes increasingly difficult for the cells to "read" the FXN gene and produce the protein required by the mitochondria, which in turn cease to function properly. One in 40,000 individuals has this condition.

The DNA repeats literally gum up the works. They can also cause other mutations in the surrounding DNA, or make chromosomes extremely fragile, breaking into pieces, or rearranging themselves. If we can shrink the DNA repetition in tissues to levels found in healthy people, we might be able to stabilize the DNA and reduce the effects of disease."
Sergei Mirkin, professor and chair, Department of Biology, School of Arts & Sciences, Tufts University

It is known that in patients' tissues, the GAA repeats are unstable and continuously expand and contract. Understanding the mechanism of GAA repeat expansion and contraction -- especially contraction -- is important to developing this strategy for battling the currently incurable disease.
Numerous theories have been advanced as to how the DNA repeats contract, although the precise details of the mechanism remained largely unknown.

In order to pinpoint the actual mechanism, the authors of the study developed an experimental system in yeast (Saccharormyces cerevisiae) to quantitatively measure the effects of different interventions on contractions of DNA repeats, and found that contractions happened usually during the process of DNA replication, in the course of what is referred to as "lagging strand synthesis."

When the two strands of DNA are copied, one strand is replicated in a continuous manner, while the other must be assembled from smaller pieces stitched together.

This is the lagging strand, so named because its more complex synthesis limits the rate at which the DNA can be copied.

The Tufts researchers found that the contraction of repeats depends on the ability of the DNA repeat to form an unusual triple-helical DNA structure along the laggin strand.

The normal structure of DNA is a double helix consisting of two strands winding around each other. A triple helix, in contrast, consists of three strands wrapped in a helical twist.

As the replication machinery moves across the lagging strand, it cannot easily bypass a triplex formed by the repeat.

When the replication machinery jumps over this triple helix hurdle, the copied DNA strand ends up with fewer GAA repeats.

"While these results were uncovered in a yeast model, they do provide us with a clue into the mechanism of DNA repeat instability in Friedreich's ataxia," said Alexandra Khristich, graduate student in Mirkin's lab and first author of the study.

"I hope that our discovery would become a starting point for the potential development of therapeutic strategies that tip the balance toward DNA repeat contraction in patient tissues."

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