Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

NMDA receptors

Alternative model for Alzheimer’s neurodegeneration

In recent debate over the FDA’s approval of the Alzheimer’s drug aducanumab, we’ve heard a lot about the “amyloid hypothesis.” In that context, it’s refreshing to learn about a model of Alzheimer’s neurodegeneration that doesn’t start with the pathogenic proteins amyloid or Tau.

Instead, a new paper in Alzheimer’s & Dementia from Emory neuroscientist Shan Ping Yu and colleagues focuses on an unusual member of the family of NMDA receptors, signaling molecules that are critical for learning and memory. Their findings contain leads for additional research on Alzheimer’s, including drugs that are already FDA-approved that could be used preventively, and genes to look at for risk factors.

“It’s not just another rodent model of Alzheimer’s,” Yu says. “We are emphasizing a different set of mechanisms leading to neurodegeneration.”

Read more

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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.

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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).

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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

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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

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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.

ajhg-fig-2-092016

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.

steveandhongjie

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.

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.

 

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