Beyond birthmarks and beta blockers, to cancer prevention

Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol. Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead Read more

Drying up the HIV reservoir

Wnt is one of those funky developmental signaling pathways that gets re-used over and over again, whether it’s in the early embryo, the brain or the Read more

Overcoming cardiac pacemaker "source-sink mismatch"

Instead of complication-prone electronic cardiac pacemakers, biomedical engineers at Georgia Tech and Emory envision the creation of “biological Read more

neuroscience

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

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Probing hyperexcitability in fragile X syndrome

Researchers at Emory University School of Medicine have gained insight into a feature of fragile X syndrome, which is also seen in other neurological and neurodevelopmental disorders.

In a mouse model of fragile X syndrome, homeostatic mechanisms that would normally help brain cells adjust to developmental changes don’t work properly. This helps explain why cortical hyperexcitability, which is linked to sensory sensitivity and seizure susceptibility, gradually appears during brain development.

Studying a model of fragile X syndrome, Emory researchers were looking at neurons displaying single spiking and multi-spiking behavior. 

These physiological insights could help guide clinical research and efforts at early intervention, the scientists say. The results were published Feb. 5 by Cell Reports (open access).

Fragile X syndrome is the most common inherited form of intellectual disability and a leading single-gene cause of autism. Individuals with fragile X syndrome often display sensory sensitivity and some — about 15 percent— have seizures.

Scientists’ explanation for these phenomena is cortical hyperexcitability, meaning that the response of the cortex (the outer part of the brain) to sensory input is more than typical. Cortical hyperexcitability has also been observed in the broader category of autism spectrum disorder, as well as migraine or after a stroke.

At Emory, graduate student Pernille Bülow forged a collaboration between Peter Wenner, PhD and Gary Bassell, PhD. Wenner, interested in homeostatic plasticity, and Bassell, an expert in fragile X neurobiology, wanted to investigate why a mechanism called homeostatic intrinsic plasticity does not compensate for the changes in the brain brought about in fragile X syndrome. More here.

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Vulnerability to stress – Tet by Tet

Geneticist Peng Jin and colleagues have a paper in Cell Reports this week that is part of a mini-boom in studying the Tet enzymes and their role in the brain. The short way to explain what Tet enzymes do is that they remove DNA methylation by oxidizing it out.

Methylation, a modification of DNA that generally shuts genes off, has been well-studied for decades. The more recent discovery of how cells remove methylation with the Tet enzymes opened up a question of what roles the transition markers have. It’s part of the field of epigenetics: the meaning of these modifications “above” the DNA sequence.

This is my favorite analogy to explain the transition states, such as 5-hydroxymethylcytosine. They’re not really a new letter of the genetic alphabet – they’ve been there all along. We just didn’t see them before.

Imagine that you are an archeologist, studying an ancient civilization. The civilization’s alphabet contains a limited number of characters. However, an initial pass at recently unearthed texts was low-resolution, missing little doodads like the cedilla in French: Ç.

Are words with those marks pronounced differently? Do they have a different meaning?

The new Cell Reports paper shows that it matters what pen writes the little doodads. In mice, removing one Tet enzyme, Tet1, has the opposite effect from removing Tet2, when it comes to response to chronic stress. One perturbation (loss of Tet1) makes the mice more resistant to stress, while the other (loss of Tet2) has them more vulnerable. The researchers also picked up an interaction between Tet1 and HIF1-alpha, critical for regulation of cells’ response to hypoxia. Read more

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Cells in “little brain” have distinctive metabolic needs

Cells’ metabolic needs are not uniform across the brain, researchers have learned. “Knocking out” an enzyme that regulates mitochondria, cells’ miniature power plants, specifically blocks the development of the mouse cerebellum more than the rest of the brain.

The results were published in Science Advances.

“This finding will be tremendously helpful in understanding the molecular mechanisms underlying developmental disorders, degenerative diseases, and even cancer in the cerebellum,” says lead author Cheng-Kui Qu, MD, PhD, professor of pediatrics at Emory University School of Medicine, Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta.

The cerebellum or “little brain” was long thought to be involved mainly in balance and complex motor functions. More recent research suggests it is important for decision making and emotions. In humans, the cerebellum grows more than the rest of the brain in the first year of life and its development is not complete until around 8 years of age. The most common malignant brain tumor in children, medulloblastoma, arises in the cerebellum.

Qu and his colleagues have been studying an enzyme, PTPMT1, which controls the influx of pyruvate – a source of energy derived from carbohydrates – into mitochondria. They describe pyruvate as “the master fuel” for postnatal cerebellar development.

Cells can get energy by breaking down sugar efficiently, through mitochondria, or more wastefully in a process called glycolysis. Deleting PTPMT1 provides insight into which cells are more sensitive to problems with mitochondrial metabolism. A variety of mitochondrial diseases affect different parts of the body, but the brain is especially greedy for sugar; it never really shuts off metabolically. When someone is at rest, the brain uses a quarter of the body’s blood sugar, despite taking up just 2 percent of body weight in an adult. More here.

Also, see this 2017 item from Stanford on the cerebellum (Nature paper).

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Looking ahead to new opioid treatments

Stephanie Foster sees herself one day specializing in addiction psychiatry. When she started her MD/PhD studies at Emory, she sought out neuroscientist David Weinshenker to discuss research projects. She is now examining potential treatments for opiate addiction based on galanin, a neuropeptide found in the brain.

Weinshenker and his colleagues had already been studying galanin in relation to stimulants such as cocaine. Preliminary studies in animals indicate that activating galanin signals might reduce the rewarding effects of opiates, withdrawal symptoms, and relapse-like behavior.

“This was a whole new direction that looked promising,” Foster says. “But first, we have to work out the brain circuitry.”

Foster comes from a Native American background, and has a long-range plan to work in the Indian Health Service. The death rate of Native Americans from opiate overdoses is the highest of any American population group, according to the Centers for Disease Control and Prevention. She would like to establish a research lab in a region of the country where she could continue her addiction research and also work closely with Native communities.

Screenshot from NIH reporter (grant database). F31 grants for year 2018.

Last year, Foster applied for and received an individual grant from the National Institute on Drug Abuse to support her work. Emory currently leads U.S. universities in the number of graduate students holding their own active grants from the National Institutes of Health. This reflects a multi-year effort to build instruction in critical parts of scientific life: planning and communicating about one’s work.

With opiate addiction, convincing others that the topic is worthwhile is not so difficult. Foster notes that few treatments are available for the early stages of opiate addiction. Long-lasting opiate substitutes/replacements such as methadone and buprenorphine are used once dependence has set in, and another medication, lofexidine, was recently approved for acute withdrawal symptoms.

“There isn’t really anything for people before they reach that stage,” Foster says. “Our idea is to look for an intervention that could be given earlier.” Read more

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Fragile X: preclinical portfolio for PI3k drug strategy

Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

Video from the iBook “Basic Science Breakthroughs: Fragile X Syndrome”. Narration by Emory genetics chair Stephen Warren, whose team identified the gene responsible for fragile X.

“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”

The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.

While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.

With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.

Warren played a major role in developing the mGluR5 approach and Emory investigators were part of those studies. More recently, clinical trials for one of the mGluR5 medications were revived in younger children and Emory is a participating site. Also, see this 2016 discussion in Spectrum with Elizabeth Berry-Kravis on the fragile X mouse model; Bassell, Gross and Gourley have made some inroads on the limitations Berry-Kravis describes.

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The blue spot: where seeds of destruction begin

Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.

The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.

Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons

The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.

“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more

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An exceptional electrical thrill ride #CNS2018

A recent paper in Neuropsychologia got a lot of attention on Twitter and at the Cognitive Neuroscience Society meeting in Boston over the weekend. It discusses what can happen when the amygdala, a region of the brain known for regulating emotional responses, receives direct electrical stimulation. A thrill ride – but for only one study participant. Two of nine people noticed the electrical stimulation. One individual reported (a video is included in the paper):

“It was, um, it was terrifying, it was just…it was like I was about to get attacked by a dog. Like the moment, like someone unleashes a dog on you, and it’s just like it’s so close…

He also spontaneously reported “this is fun.” He further explained that he could distinguish feelings in his body that would normally be associated with fear recognized and the absence of an actual threat, making the experience “fun”.

But wait, why were Emory neuroscientists Cory Inman, Jon Willie and Stephan Hamann and colleagues doing this? Read more

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Epilepsy pick up sticks

Imagine the game of pick up sticks. It’s hard to extract one stick from the pile without moving others. The same problem exists, in a much more complex way, in the brain. Pulling on one gene or neurotransmitter often nudges a lot of others.

Andrew Escayg, PhD

That’s why a recent paper from Andrew Escayg’s lab is so interesting. He studies genes involved in epilepsy. Several years ago, he showed that mice with mutations in the SCN8A gene have absence epilepsy, while also showing resistance to induced seizures. SCN8A is one of those sticks that touches many others. The gene encodes a voltage-gated sodium channel, involved in setting the thresholds for and triggering neurons’ action potentials. Mutating the gene in mice modifies sleep and even enhances spatial memory.

Escayg’s new paper, with first author Jennifer Wong, looks at the effect of “knocking down” SCN8A in the hippocampus in a mouse model of mesial temporal lobe epilepsy. This model doesn’t involve sodium channel genes; it’s generated by injection of a toxin (kainic acid) into the brain. The finding suggests that inhibiting SCN8A may be applicable to other forms of epilepsy. Escayg notes that mesial temporal lobe epilepsy is one of the most common forms of treatment-resistant epilepsy in adults.

Knocking down SCN8A in the hippocampus 24 hours after injection could prevent the development of seizures in 90 percent of the treated mice. “It is likely that selective reduction in Scn8a expression would have directly decreased neuronal excitability,” the authors write. It did not lead to increased anxiety levels or impaired learning/memory.

Currently, no available drugs target Scn8a specifically. However, antisense approaches for neurodegenerative diseases have been gaining ground – perhaps epilepsy could fit in.

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Insight into brain + learning via ‘friend of fragile X’ gene

We can learn a lot about somebody from the friends they hang out with. This applies to people and also to genes and proteins. Emory scientists have been investigating a gene that we will call — spoiler alert — “Friend of fragile X.”

Fragile X syndrome is the most common inherited form of intellectual disability, studied by research teams around the world with drug discovery and clinical trials in mind. It is caused by a disruption of the gene FMR1.

In an independent form of inherited intellectual disability found in a small number of Iranian families, a gene called ZC3H14 is mutated. Two papers from Ken Moberg, PhD, associate professor of cell biology, Anita Corbett, PhD, professor of biology and colleagues show that FMR1 and ZC3H14 are, in effect, friends.

The findings provide new insight into the function of FMR1 as well as ZC3H14; the evidence comes from experiments performed in fruit flies and mice. The most recent paper is in the journal Cell Reports (open access), published this week.

The scientists found that the proteins encoded by FMR1 and ZC3H14 stick together in cells and they hang out in the same places. The two proteins have related functions: they both regulate messenger RNA in neurons, which explains their importance for learning and memory.

The fragile X protein (FMRP) was known to control protein production in response to signals arriving in neurons, but the Cell Reports paper shows that FMRP is also regulating the length of  “tails” attached to messenger RNAs – something scientists did not realize, even after years of studying FMRP and fragile X, Moberg says.

To be sure, FMRP interacts with many proteins and appears to be a critical gatekeeper. Emory geneticist Peng Jin, who has conducted his share of research on this topic, says that “FMRP must be very social and has a lot of friends.” More here.

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