Traynelis lead researcher on CureGRIN/Chan Zuckerberg award

Congratulations to the CureGRIN Foundation, which was recently awarded a capacity-building grant from the Chan Zuckerberg Initiative’s Rare as One Network. The Chan Zuckerberg Initiative is giving 30 patient advocacy groups such as CureGRIN $450,000 each over two years.

CureGRIN works closely with Emory pharmacologist Stephen Traynelis, who has been investigating rare genetic disorders affecting NMDA receptors, which play key roles in memory, learning and neuronal development. When NMDA receptor function is perturbed by mutations, symptoms appear in infancy or early childhood, usually including epilepsy and developmental delay.

For the grant, Traynelis is named as the lead researcher for the CureGRIN Foundation, with Tim Benke of Children’s Hospital Colorado as lead clinician. Traynelis is director of the Center for Functional Evaluation of Rare Variants, which hosted a gathering at Emory Conference Center that brought together several GRIN-oriented patient advocacy groups in September 2019.

Posted on February 19, 2020 by Quinn Eastman in Neuro Leave a comment

More NMDA but less excitotoxicity? Now possible

Emory pharmacologists have discovered a new class of potential drugs that might allow them to have their cake and eat it too — with reference to NMDA receptors, important control sites in the brain for learning and memory.

Many researchers have wanted to enhance NMDA receptor signals to treat disorders such as schizophrenia. But at the same time, they need to avoid killing neurons with “excitotoxicity”, which comes from excess calcium entering the cell. Excitotoxicity is thought to be a major mechanism of cell death in stroke and traumatic brain injury.

Usually more sensitivity to NMDA activation and excess calcium go hand in hand. In a new Nature Chemical Biology paper, pharmacologist Stephen Traynelis and colleagues have identified a group of compounds that allow them to separate those two aspects of NMDA signaling.

These compounds appear to selectively decrease how much calcium (as opposed to sodium) flows through the NMDA ion channel. Traynelis says that the discovery opens up pharmacological possibilities for NMDA receptors similar to those for other receptor classes that are prominent drug targets, such as G-protein coupled receptors and acetylcholine receptors. With such receptors, the drugs are called “biased agonists” or “biased modulators” because they shift the balance of how the ion channel responds.

For NMDA receptors, how these newly identified compounds work on a molecular level needs to be explored, and could lead to the long-standing goal of NMDA-based neuroprotection for treatment of stroke/TBI, the authors note. Postdoc Riley Perszyk is first author, with cell biologist Gary Bassell and chemists Dennis Liotta and Lanny Liebeskind as co-authors.

Traynelis discussed this research in his Hodgkin Huxley Katz Prize Lecture to the Physiology 2019 conference in Scotland in December 2019 (the part about the new class of NMDA modulators starts at about 20 minutes).

Posted on January 24, 2020 by Quinn Eastman in Neuro Leave a comment

GRIN families join together for neuroscience

Editor’s note: This post was a collaboration with MMG graduate student Megan Hockman.

They were brought together by their children’s epilepsies, and by rapid advances in genetic sequencing. Only a few years ago, these families would have been isolated, left to deal with their children’s seizures and neurological problems on their own. Now, they’ve organized themselves and are shaping the future of research.

Agonist binding domains of NMDA receptors, where several disease-causing mutations can be found. Adapted from Swanger et al, AJHG (2016).

In mid-September, parents of children affected by variations in GRIN genes gathered at Emory Conference Center to meet with scientists to discuss current research. GRIN disorders occur because of mutations in genes encoding NMDA receptors, which play key roles in memory, learning and neuronal development. NMDA receptors are a type of receptor for glutamate, the main excitatory neurotransmitter in the brain. The receptors themselves are encoded by multiple genes and assemble into tetramers. When their function is altered by mutations in one of these genes, symptoms appear in infancy or early childhood, usually including epilepsy and developmental delay.

The conference was the first time several patient advocacy groups oriented around GRIN-related disorders had met together, says Denise Rehner, president of the CureGRIN Foundation and mother of an affected child. For parents, this was an opportunity to connect with each other and advocacy groups, and to interact with scientists. For researchers, it was a chance to hear from those who are being impacted by their studies, and to discuss better ways to share data.

“We got a chance to explain to all the stakeholders – patient groups, foundations, companies – exactly what we do,” said Emory neuroscientist and conference organizer Stephen Traynelis, director of the Center for Functional Evaluation of Rare Variants. Traynelis and colleague Hongjie Yuan have been tracking the direct impacts of mutations on the function of the NMDA receptor. In doing so, they plan work with clinicians to compile registries, linking specific functional data to patient symptoms.

In addition to understanding underlying mechanisms and outcomes of GRIN disorders, researchers want to figure out how to treat affected children with existing drugs. Several options exist for targeting NMDA receptors, such as dextromethorphan (a cough suppressant) or memantine, approved for symptoms of Alzheimer’s. Traynelis and Yuan previously collaborated with the Undiagnosed Disease Program (now the Undiagnosed Disease Network) at the National Institutes of Health to investigate memantine as a treatment for a child with a GRIN2A mutation, showing that the drug could reduce seizure burden in one patient. Read more

Posted on September 30, 2019 by Quinn Eastman in Neuro Leave a comment

Complexity of NMDA receptor drug discovery target revealed

Know your target. Especially if your target is coming into focus for treating diseases such as schizophrenia and treatment-resistant depression.

NMDA receptors, critical for learning and memory, are sensors in the brain. Studying them in molecular detail is challenging, because they usually come in four parts, and the parts aren’t all the same.

Researchers at Emory have been probing one variety of NMDA receptor assembly found in the cerebellum, and also in the thalamus, a central gateway for sensory inputs, important for cognition, movement and sleep. This variety includes a subunit called GluN2C – together with two partners, GluN1 and GluN2A.

The results were published Thursday, June 28 in Neuron.

Outside of a living brain, NMDA receptor assemblies are typically studied with either two copies of GluN2C or two of GluN2A, but not with one of each, says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine

“Our data suggest that GluN2C is rarely by itself,” Traynelis says. “It’s typically paired up with another GluN2 subunit. This means we really don’t know what the properties of the main NMDA receptor in the cerebellum or the thalamus are.”

Psychiatrists have become interested in GluN2C because it appears to decline in the brains of schizophrenia patients. Mice without adequate levels of GluN2C display abnormalities in learning, memory and sensory processing, which together resemble schizophrenia in humans. In addition, GluN2C appears to be important for the mechanism of ketamine, a drug being studied for its rapid anti-depressant effects.

Using drugs that are selective for particular combinations of NMDA receptor subunits, Traynelis’ laboratory showed that an assembly of GluN2A and GluN2C is the dominant form in the mouse cerebellum. When GluN2C is introduced into cortical neurons, it prefers to pair up with GluN2A, the researchers found. This raises the question, in regions such as the thalamus, of whether GluN2C also appears with a partner GluN2 subunit. They also observed that the GluN2A-GluN2C assembly has distinct electrochemical properties. Read more

Posted on July 2, 2018 by Quinn Eastman in Neuro Leave a comment

More on NMDA receptor variants + epilepsy/ID

NMDA receptors are complex electrochemical machines, important for signaling between brain cells. Rare mutations in the corresponding genes cause epilepsy and intellectual disability.

Pre-M1 helices in multi-subunit NMDA receptor. Adapted from Ogden et al PLOS Genetics (2017).

In Emory’s Department of Pharmacology, the Traynelis and Yuan labs have been harvesting the vast amounts of information now available from public genome databases, to better understand how changes in the NMDA receptor genes relate to function. (Take a “deeper dive” into their November 2016 publication on this topic here.)

Their recent paper in PLOS Genetics focuses on a particular region in the NMDA receptor, called the pre-M1 helix (see figure). It also includes experiments on whether drugs now used for Alzheimer’s disease, such as memantine, could be repurposed to have beneficial effects for patients with certain mutations. The in vitro data reported here could inform clinical use. Read more

Posted on January 31, 2017 by Quinn Eastman in Neuro Leave a comment

Nerve gas, angel dust and genetic epilepsy

Last week, Lab Land noticed similarities between two independent lines of research from the Escayg and Traynelis/Yuan labs at Emory. Both were published recently and deal with rare forms of genetic epilepsy, in which molecular understanding of the cause leads to individualized treatment, albeit with limited benefit.

Both conditions are linked to an excess of neuronal excitation, and both can be addressed using medications that have also been tested for Alzheimer’s. A critical difference is that memantine is FDA-approved for Alzheimer’s, but huperzine A is not.

What condition?	Dravet syndrome/GEFS+	Epilepsy-aphasia syndrome
What gene is mutated?	SCN1A – sodium ion channel	GRIN2A – NMDA receptor subunit
What is the beneficial drug?	Huperzine A	Memantine
How does the drug work?	Acetylcholinesterase inhibitor	NMDA receptor antagonist
Other drugs that use the same mechanism	Alzheimer’s medications such as donepezil Irreversible + stronger: insecticides, nerve gas	Ketamine, phencyclidine (aka PCP)

Posted on November 16, 2016 by Quinn Eastman in Neuro Leave a comment

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 2 Comments

Reviving drugs with anti-stroke potential, minus side effects

Neuroprotective drugs might seemÂ impractical or improbable right now, after twoÂ big clinical trials testing progesterone in traumatic brain injury didn’t work out. But oneÂ close observer of drug discovery isÂ predicting a “coming boom in brain medicines.” Maybe this research, which Emory scientists have been pursuing for a long time, will be part of it.

In the 1990s, neuroscientists identified a class of drugs that showed promise in the area of stroke. NMDA receptor antagonists could limit damage to the brain in animal models of stroke. But one problem complicated testing the drugs in a clinical setting: the side effects included disorientation and hallucinations.

Now researchers have found a potential path around this obstacle. The results were published in Neuron.

â€œWe have found neuroprotective compounds that can limit damage to the brain during ischemia associated with stroke and other brain injuries, but have minimal side effects,â€ says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine.

â€œThese compounds are most active when the pH is lowered by biochemical processes associated with injury of the surrounding tissue. This is a proof of concept study that shows this mechanism of action could potentially be exploited clinically in several conditions, such as stroke, traumatic brain injury and subarachnoid hemorrhage.â€ Read more

Posted on February 27, 2015 by Quinn Eastman in Neuro Leave a comment

Lab Land looking back: Top ten themes for 2014

It is a privilege to work at Emory and learn about and report on so much quality biomedical research. I started to make a top 10 for 2014 and had too many favorites. After divertingÂ some of these topics into the 2015 crystal ball,Â I corralledÂ them into themes.

1. Cardiac cell therapy

PreSERVE AMI clinical trial led by cardiologist Arshed Quyyumi. Emory investigators developingÂ a variety ofÂ approaches to cardiac cell therapy.

2. Mobilizing the body’s own regenerative potential

Ahsan Husain’s work on how young hearts grow. Shan Ping Yu’s lab usingÂ parathyroid hormone boneÂ drug to mobilize cells for stroke treatment.

3. Epigenetics

Many colors in the epigenetic palette (hydroxymethylation). Valproate – epigenetic solventÂ (anti-seizure –> anti-cancer). Methylation in atherosclerosis model (Hanjoong Jo). How to write conservatively about epigenetics and epigenomics.

4. Parkinson’s disease therapeutic strategies

Container Store (Gary Miller, better packaging for dopamine could avoidÂ stress to neurons).

Anti-inflammatory (Malu Tansey, anti-TNF decoy can passÂ blood-brain barrier).

5. Personal genomics/exome sequencing

Rare disease diagnosisÂ featured in the New Yorker. Three–part series on patient with GRIN2AÂ mutation.

6. Neurosurgeons, likeÂ Emory’s Robert Gross and Costas Hadjpanayis, do amazing things

7. Fun vsÂ no fun

Fun = writing about Omar from The Wire in the context of drug discovery.

No fun (but deeply moving) = talking with patientsÂ fighting glioblastoma.

8. The hypersomnia field is waking up

Our Web expert tells me this was Lab Land’s most widely read post last year.

9. Fine-tuning approaches to cancer

Image guided cancer surgery (Shuming Nie/David Kooby).Â Cancer immunotherapy chimera (Jacques Galipeau). Fine tuning old school chemo drug cisplatin (Paul Doetsch)

10. Tie between fructose effects on adolescent brain (Constance Harrell/Gretchen Neigh) and flu immunology (embrace the unfamiliar! Ali Ellebedy/Rafi Ahmed)

Posted on January 7, 2015 by Quinn Eastman in Uncategorized Leave a comment

NMDA receptors: triple-quadruple axel

NMDA receptors are saddled with an unwieldy name, but they are some of the most important* signaling molecules in the brain, both for learning and memory and in neurological and psychiatric diseases.

Kasper Hansen, a postdoc from Stephen Traynelis’ lab who is establishing his own at the University of Montana, is lead author on a recent paper in Neuron, which could spur research on NMDA receptors’ pharmacological properties.

The NMDA receptors in the brain are actually mix-and-match assemblies of four subunits, and most of the time in the brain, three different proteins come together to make one receptor, the authors explain. In the laboratory, it has been easier to study simpler, more homogenous, but also more artificial constructs. Hansen and his colleagues developed a way to build replicas of the more complicated NMDA receptors found in the brain and probe their distinct responses to drugs. Read more

Posted on March 6, 2014 by Quinn Eastman in Neuro Leave a comment

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