Deep dive into NMDA receptor variation

The study of human genetics has often focused on mutations that cause disease. When it comes to genetic variations in healthy people, scientists knew they were out there, but didn’t have a full picture of their extent. That is changing with the emergence of resources such as the Exome Aggregation Consortium or ExAC, which combines sequences for the protein-coding parts of the genome from more than 60,000 people into a database that continues to expand.

Rare mutations in the NMDA receptor genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). Shown in blue are agonist binding domains of the receptors, where several disease-causing mutations can be found.

At Emory, the labs of Stephen Traynelis and Hongjie Yuan have published an analysis of ExAC data, focusing on the genes encoding two NMDA receptor subunits, GRIN2A and GRIN2B. These receptors are central to signaling between brain cells, and rare mutations in the corresponding genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). GRIN2B mutations have also been linked with autism spectrum disorder.

Steve Traynelis and Hongjie Yuan

The new paper in the American Journal of Human Genetics makes a deep dive into ExAC data to explore the link between normal variation in the healthy population and regions of the proteins that harbor disease-causing mutations.

In addition, the paper provides a detailed look at how 25 mutations that were identified in individuals with neurologic disease actually affect the receptors. For some patients, this insight could potentially guide anticonvulsant treatment with a repurposed Alzheimer’s medication. Also included are three new mutations from patients identified by whole exome sequencing, one in GRIN2A and two in GRIN2B.

“This is one of the first analyses like this, where we’re mapping the spectrum of variation in a gene onto the structure of the corresponding protein,” says Traynelis, PhD, professor of pharmacology at Emory University School of Medicine. “We’re able to see that the disease mutations cluster where variation among the healthy population disappears.”

Heat map of agonist binding domain for GRIN2A. From Swanger et al AJHG (2016).

Postdoctoral fellow Sharon Swanger, PhD is first author of the paper, and Yuan, MD, PhD, assistant professor of pharmacology, is co-senior author.

It’s not always obvious, looking at the sequence of a given mutation, how it’s going to affect NMDA receptor function. Only introducing the altered gene into cells and studying protein function in the lab provides that information, Traynelis says.

NMDA receptors are complicated machines: mutations can affect how well they bind their ligands (glutamate and glycine), how they open and shut, or how they are processed onto the cell surface. On top of that complexity, mutations that make the receptors either stronger or weaker can both lead the brain into difficulty; within each gene, both types of mutation are associated with similar disorders. With some GRIN2A mutations, the functional changes identified in the lab were quite strong, but the effect on the brain was less dramatic (mild intellectual disability or speech disorder), suggesting that other genetic factors contribute to outcomes.

Clinical relevance

Traynelis and Yuan previously collaborated with the NIH’s Undiagnosed Disease Program to show that the Alzheimer’s medication memantine can be repurposed as an anticonvulsant, for a child with intractable epilepsy coming from a mutation in the GRIN2A gene. (Nature Communications, Annals of Clinical and Translational Neurology)

Memantine is an NMDA receptor antagonist, aimed at counteracting the overactivation of the receptor caused by the mutation. Memantine has also been used to treat children with epilepsy associated with mutations in the related GRIN2D gene. However, memantine doesn’t work on all activating mutations, and could have effects on the unmutated NMDA receptors in the brain as well. Traynelis reports that his clinical colleagues are developing guidelines for physicians on the use of memantine for children with GRIN gene mutations.

This study and related investigations were supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD082373), the National Institute of Neurological Disorders and Stroke (R24NS092989), the Atlanta Clinical & Translational Science Institute (UL1TR000454), and CURE Epilepsy: Citizens United for Research in Epilepsy.

Posted on November 11, 2016 by Quinn Eastman in Neuro Leave a comment

Blood versus the crypts

Amielle Moreno

For Halloween, Lab Land welcomes a guest post from Neuroscience graduate student Amielle Moreno, former editor of the Central Sulcus newsletter.

While recent studies have found evidence for the healing properties of blood from younger individuals, the fascination with “young blood” has been a part of the human condition for centuries.

In ancient Greece, Hippocrates introduced the concept that our health and temperament was controlled by the four humors, proposing that blood was the one responsible for courage, playfulness as well as hope. From the 16^th century story of Countess Elizabeth Báthory de Ecsed of Hungary, the idea of “blood baths” acquired decidedly more sinister connotations.

The “Blood Countess” holds the Guinness World Record as the most prolific female murderer. With 80 confirmed kills, Báthory might have lured up to 650 peasant girls to her castle with the promise of work as maidservants or courtly training. Instead of etiquette lessons, they were burned, beaten, frozen or starved for the Countess’ sadistic pleasure. Folk stories told how she would bathe in the blood of virgins to preserve her youth and beauty.

Portrait if Elizabeth Bathory, via Wikimedia

Humors remained a staple of traditional western medicine until the 1800s when medical research and our modern concept of medicine emerged. In this more enlightened age, people started sewing animals together to see what would happen.

In the mid-1800s, a French zoologist named Paul Bert first experimented with the creation of parabionts: the surgical joining of two animals, usually two rodents of the same species, in order to study the effect of one’s blood on the other. Read more

Posted on October 30, 2016 by Quinn Eastman in Heart, Immunology, Neuro Leave a comment

How metabolic syndrome interacts with stress – mouse model

Emory researchers recently published a paper in Brain, Behavior and Immunity on the interaction between psychological stress and diet-induced metabolic syndrome in a mouse model.

“The metabolic vulnerability and inflammation associated with conditions present in metabolic syndrome may share common risk factors with mood disorders. In particular, an increased inflammatory state is recognized to be one of the main mechanisms promoting depression,” writes lead author Betty Rodrigues, a postdoc in Malu Tansey’s lab in the Department of Physiology.

This model may be useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders. As a follow-up, Tansey reports that her team is investigating the protective effects of an anti-inflammatory agent on both the brain and the liver using the same model.

Metabolic syndrome and stress have a complex interplay throughout the body, the researchers found. For example, psychological stress by itself does not affect insulin or cholesterol levels, but it does augment them when combined with a high-fat, high-fructose diet. In contrast, stress promotes adaptive anti-inflammatory markers in the hippocampus (part of the brain), but those changes are wiped out by a high-fat, high-fructose diet.

The findings show synergistic effects by diet and stress on gut permeability promoted by inflammation, and the biliverdin pathway. Biliverdin, a product of heme breakdown, is responsible for a greenish color sometimes seen in bruises.

“Stress and high-fat high-fructose diet promoted disturbances in biliverdin, a metabolite associated with insulin resistance,” Rodrigues writes. “To the best of our knowledge, our results reveal for the first time evidence for the synergistic effect of diet and chronic psychological stress affecting the biliverdin pathway.”

Posted on October 20, 2016 by Quinn Eastman in Heart, Immunology, Neuro Leave a comment

Let’s not elope

Elopement may sound cute, because the word evokes a starry-eyed couple running away to get married. Elopement also refers to when a child runs or wanders from a safe, supervised environment. It can be a worrisome concern among the parents and caregivers of children with autism spectrum disorder and/or intellectual disability.

Here is a straightforward post from Seattle Children’s on elopement. Cathy Rice, now director of Emory Autism Center and previously at the CDC, has published two papers on elopement.

This May, Nathan Call, director of Severe Behavior Programs at Marcus Autism Center, and colleagues published a retrospective review of their behavioral treatments for elopement, extending back to 2003. This is a companion to their 2015 analysis of treatment for pica, the ingestion of inedible substances. Call is also assistant professor of pediatrics at Emory University School of Medicine.

He summarized their approach by saying: “Individualizing treatment based upon the reason each child elopes seems to work very well.” The paper makes it clear that the reasons for a child eloping were a mixed bag: for some it was “access to preferred tangible items,” for others it was access to attention or other reasons.

Elopement can be difficult to study scientifically because the consequences of just letting it happen may be disastrous. In an interview, Call described one child who was attracted by balloons. He eloped so readily that he had been struck by cars twice, one time because he was drawn to a balloon display at a nearby apartment complex.

The 11 children in the review were ages 5 to 12, and 7 had a diagnosis of autism spectrum disorder – others had Down syndrome or intellectual disability. Read more

Posted on October 14, 2016 by Quinn Eastman in Neuro Leave a comment

A glimpse into the genetics of positive emotions

Happiness can be elusive, both in personal life and as a scientific concept. That’s why this paper, recently published in Molecular Psychiatry, seemed so striking.

“A genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs.” Translation: a glimpse into the genetics of positive emotions.

Editorial note: Although the research team here is careful and confirms the findings in independent groups and in brain imaging and fear discrimination experiments, this is a preliminary result. More needs to be explored about how these genetic variants and others affect positive emotions.

“With relatively few studies on genetic underpinnings of positive emotions, we face the challenges of a nascent research area,” the authors write.

Perhaps ironically, the finding comes out of the Grady Trauma Project, a study of inner-city residents exposed to high rates of abuse and violence, aimed at understanding mechanisms of resilience and vulnerability in depression and PTSD.

“Resilience is a multidimensional phenomenon, and we were looking at just one aspect of it,” says first author Aliza Wingo. She worked with Kerry Ressler , now at Harvard, and Tanja Jovanovic and other members of the Grady Trauma Project team.

“Positive affect” is what the team was measuring, through responses on questionnaires. And the questions are asking for the extent that respondents feel a particular positive emotion in general, rather than that day or that week. Read more

Posted on October 12, 2016 by Quinn Eastman in Neuro Leave a comment

Sensory connections spill over in synesthesia

Neuroscientists at Emory University have found that people who experience a mixing of the senses, known as synesthesia, are more sensitive to associations everyone has between the sounds of words and visual shapes. The results are published in the European Journal of Neuroscience.

Synesthesia is a stable trait, and estimated to be present in 1 to 4 percent of people. It can be inherited, although the precise genes have not been identified. One of the most common forms of synesthesia is when people involuntarily see particular colors in connection with letters, numbers or sounds.

Many artists and composers have described their experiences with synesthesia. Children with synesthesia say sometimes that it is distracting when they are trying to read. Thus, understanding the origins of synesthesia may help people with dyslexia or other learning differences, or people who have lost their sight or hearing and are trying to engage in sensory substitution for rehabilitation.

Researchers led by neurologist Krish Sathian, MD, PhD, recruited 17 people with synesthesia, and asked them to take a form of the IAT (implicit association test). Known for its use probing social attitudes such as racial prejudice, the IAT can also assess “cross-modal correspondences.”

An example of a cross-modal correspondence is that we describe musical notes as being “high” or “low” – words that also signify relative positions in space. Another is that we think of some sounds such as “m” and “l” as soft, and are more likely to associate them with rounded shapes. Similarly, we connect hard sounds such as “k” and “t” with angular shapes.

“There’s been a debate about synesthesia,” Sathian says. “Are the associations synesthetes have just extreme versions of cross-modal correspondences that other people have, or are they qualitatively different?”

Sathian and his colleagues found that people with synesthesia were more sensitive to correspondences between the sounds of pseudowords — words without meaning in English — and rounded or angular shapes. Read more

Posted on September 12, 2016 by Quinn Eastman in Neuro Leave a comment

Strain differences in Zika infection genes

Scientists have revealed molecular differences between how the African and Asian strains of Zika virus infect neural progenitor cells. The results could provide insights into the Zika virus’ recent emergence as a global health emergency, and also point to inhibitors of the p53 pathway as potential leads for drugs that could protect brain cells from cell death.

The findings, from the Emory/Johns Hopkins/Florida State team that showed this spring that neural progenitor cells are particularly vulnerable to Zika infection (related paper), were published this week in Nucleic Acid Research. The manuscript was also posted on BioRxiv before publication.

Overlap in gene expression changes when neural progenitor cells are infected by African or Asian strains of Zika virus. Diagram from Nucleic Acids Research via Creative Commons.

Zika virus was first discovered in Uganda in the 1940s, and two distinct lineages of Zika diverged sometime in the second half of the 20^th century: African and Asian. The strains currently circulating in the Western Hemisphere, which have been linked to microcephaly in infants and Guillain-Barre syndrome in adults, are more closely related to the Asian lineage.

The research team catalogued and compared genes turned on and off by Asian and African strains of Zika virus, as well as dengue virus, in human neural progenitor cells. The authors describe dengue as inducing more robust changes in gene expression than either strain of Zika. Although they show that dengue can infect neural progenitor cells like Zika can, dengue infection does not stunt the cells’ growth or lead to cell death.

“This shows that the differences between Zika and dengue are not at the level of being able to infect neural progenitors, but more about the harm Zika causes when it does infect those cells,” says senior author Peng Jin, PhD, professor of human genetics at Emory University School of Medicine. Read more

Posted on September 1, 2016 by Quinn Eastman in Neuro 1 Comment

Cell therapy clinical trial in stroke

Emory neurosurgeon Robert Gross was recently quoted in a Tennessee newspaper article about a clinical trial of cell therapy for stroke. He used cautionary language to set expectations.

“We’re still in the very early exploratory phases of this type of work,” Gross told the Chattanooga Times Free Press. “In these cases, a significant area of the brain has been damaged, and simply putting a deposit of undifferentiated cells into the brain and magically thinking they will rewire the brain as good as new is naive. None of us think that.”

A more preliminary study (just 18 patients) using the same approach at Stanford and University of Pittsburgh was published this summer in Stroke, which says it was the “first reported intracerebral stem cell transplant study for stroke in North America.” The San Diego Union Tribune made an effort to be balanced in how the results were described:

Stroke patients who received genetically modified stem cells significantly recovered their mobility… Outcomes varied, but more than a third experienced significant benefit.

The newspaper articles made us curious about what these cells actually are. They’re mesenchymal stromal cells, engineered with an extra modified Notch gene. That extra gene drives them to make more supportive factors for neurons, but it doesn’t turn them into neurons. Read more

Posted on August 30, 2016 by Quinn Eastman in Neuro Leave a comment

HD monkeys display full spectrum of symptoms seen in humans

Transgenic Huntington’s disease monkeys display a full spectrum of symptoms resembling the human disease, ranging from motor problems and neurodegeneration to emotional dysregulation and immune system changes, scientists at Yerkes National Primate Research Center, Emory University report.

The results, published online in the journal Brain, Behavior and Immunity, strengthen the case that transgenic Huntington’s disease monkeys could be used to evaluate emerging treatments (such as this) before launching human clinical trials.

“Identifying emotional and immune symptoms in the HD monkeys, along with previous studies demonstrating their cognitive deficits and fine motor problems, suggest the HD monkey model embodies the full array of symptoms similar to human patients with the disease,” says Yerkes research associate Jessica Raper, PhD, lead author of the paper. Read more

Posted on July 20, 2016 by Quinn Eastman in Neuro Leave a comment

A sweet brain preserver: trehalose

It’s sweet, it’s safe, and it looks like it could save neurons. What is it? Trehalose.

Trehalose is a natural sugar.

This natural sugar is used in the food industry as a preservative and flavor enhancer (it’s in Taco Bell’s meat filling). And curiously, medical researchers keep running into trehalose when they’re looking for ways to fight neurodegenerative diseases.

A recent example from Emory’s Department of Pharmacology: Chris Holler, Thomas Kukar and colleagues were looking for drugs that might boost human cells’ production of progranulin (PGRN), a growth factor that keeps neurons healthy. Mutations in the progranulin gene are a common cause of frontotemporal dementia.

The Emory scientists discovered two leads: a class of compounds called mTOR inhibitors — the transplant drug rapamycin is one — and trehalose. The team decided to concentrate on trehalose because it increased PGRN levels in neuronal and non-neuronal cell types, unlike the mTOR inhibitors. Their results were published at the end of June in Molecular Neurodegeneration.

The team confirmed their findings by examining the effects of trehalose on cells derived from patients with progranulin mutations. This paper is the first to include results from Emory’s Laboratory of Translational Cell Biology, which was established in 2012 to facilitate this type of “disease in a dish” approach. Cell biologists Charles Easley, Wilfried Rossoll and Gary Bassell from the LTCB, and neurologists Chad Hales and William Hu from the Center for Neurodegenerative Disease are co-authors.

Posted on July 15, 2016 by Quinn Eastman in Neuro Leave a comment

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