Life-saving predictions from the ICU

Similar to the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. Read more

Five hot projects at Emory in 2017

Five hot projects at Emory in 2017: CRISPR gene editing for HD, cancer immunotherapy mechanics, memory enhancement, Zika immunology, and antivirals from Read more

Shaking up thermostable proteins

Imagine a shaker table, where kids can assemble a structure out of LEGO bricks and then subject it to a simulated earthquake. Biochemists face a similar task when they are attempting to design thermostable proteins, with heat analogous to shaking. Read more

Neuro

Vulnerability to cocaine uncovered in adolescent mouse brains

Editor’s note: Guest post from Neuroscience graduate student Brendan O’Flaherty. Companion paper to the Gourley lab’s recently published work on fasudil, habit modification and neuronal pruning.

An Emory study has discovered why teenager’s brains may be especially vulnerable to cocaine. Exposure to small amounts of cocaine in adolescence can disrupt brain development and impair the brain’s ability to change its own habits, the study suggests.

Guest post from Brendan O’Flaherty

The results were published in the April 1, 2017 issue of Biological Psychiatry, by researchers at Yerkes National Primate Research Center.

Drug seeking habits play a major role in drug addiction, says senior author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center. The first author of the paper is former Emory graduate student Lauren DePoy, PhD.

When it comes to habits, cocaine is especially sneaky. Bad habits like drug use are already very difficult to change, but cocaine physically changes the brain, potentially weakening its ability to “override” bad habits. Although adults are susceptible to cocaine’s effects on habits, adolescent brains are especially vulnerable.

“Generally speaking, the younger you are exposed to cocaine in life, the more likely you are to have impaired decision making,” Gourley says.

Shannon Gourley, PhD, in lab

To understand why adolescent brains are especially vulnerable to cocaine, the researchers studied the effects of cocaine exposure on how the mice make decisions about food.

“I think it’s pretty amazing that we can actually talk to mice in a way that allows them to talk back,” Gourley says. “And then we can utilize a pretty tremendous biological toolkit to understand how the brain works.”

Researchers injected adolescent mice five times with either saline or cocaine. Both groups of animals then grew up without access to cocaine. Researchers then trained the mice to press two buttons, both of which caused food to drop into the cage. Since both buttons rewarded the mice equally, the mice pushed each button half the time.

Over time, pushing the two buttons equally could become a habit. To test this, the researchers then played a trick on the mice. When one of the buttons was exposed, the researchers starting giving the mice food pellets for free, instead of rewarding them for button-pressing.

“What the mouse should be learning is: ‘Ah hah, wait a minute, when I have access to this button I shouldn’t respond, because my responding doesn’t get me anything,‘” Gourley says. Read more

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The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to follow. What they found could provide benefits for patients with the genetic disease myotonic dystrophy (DM) and possibly the sleep disorder idiopathic hypersomnia (IH).

The classic symptom for DM is: someone has trouble releasing their grip on a doorknob. However, the disease does not only affect the muscles. Clinicians have recognized for years that DM can result in disabling daytime sleepiness and sometimes cognitive impairments. At the Myotonic Dystrophy Foundation meeting in September, a session was held gathering patient input on central nervous system (CNS) symptoms, so that future clinical trials could track those symptoms more rigorously.

Emory scientists are investigating this aspect of DM. Cell biology chair Gary Bassell was interested in the disease, because it’s a triplet repeat disorder, similar to fragile X syndrome, yet the CNS mechanisms and symptoms are very different. In DM, an expanded triplet or quadruplet repeat produces toxic RNA, which disrupts the process of RNA splicing, affecting multiple cell types and tissues.

Rye at San Francisco myotonic dystrophy meeting. Photo courtesy of Hypersomnia Foundation.

Neurologist and sleep specialist David Rye also has become involved. Recall Rye’s 2012 paper in Science Translational Medicine, which described a still-mysterious GABA-enhancing substance present in the spinal fluid of some super-sleepy patients. (GABA is a neurotransmitter important for regulating sleep.)

In seven of those patients, his team tested the “wake up” effects of flumazenil, conventionally used as an antidote to benzodiazepines. One of those patients was an Atlanta lawyer, whose recovery was later featured in the Wall Street Journal and on the Today Show. It turns out that another one of the seven, whose alertness increased in response to flumazenil, has DM.

In an overnight sleep exam, this man slept for 12 hours straight – the longest of the seven. But an IH diagnosis didn’t fit, because in the standard “take a nap five times” test, he didn’t doze off very quickly. He became frustrated with the stimulants he was given and sought treatment elsewhere, Rye says. Lab Land doesn’t have all the details of this patient’s history, but eventually he was diagnosed with DM, which clarified his situation. Read more

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Skin disease studies go deep: depression/inflammation insight

The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could clear a path around the placebo effect.

Miller and his colleagues have been looking at the connection between inflammation and depression, whose evolutionary dimensions we have previously explored. They’ve examined the ability of inflammation-inducing treatments for hepatitis C and cancer to trigger symptoms of depression, and have shown that the anti-inflammatory drug infliximab (mainly used for rheumatoid arthritis) can resolve some cases of treatment-resistant depression. [Lots of praise for Miller in this September 2017 Nature Medicine feature.]

A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.

When it comes to approving new antidepressants, the FDA is still probably going to want a frontal assault on depression, despite provisions in the 21st Century Cures Act to broaden the types of admissible evidence.

“These studies emphasize how difficult it is to interpret findings when these drugs are treating more than one problem,” Miller says. “Better to have a simpler study with just depression.”

Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways. Two studies now underway at Emory specifically recruit patients with high levels of the inflammatory marker CRP, which Miller’s previous study showed was helpful in predicting response to infliximab.

The new paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more

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New insight into how brain cells die in Alzheimer’s and FTD

Removal of a regulatory gene called LSD1 in adult mice induces changes in gene activity that look unexpectedly like Alzheimer’s disease, scientists have discovered.

Researchers also discovered that LSD1 protein is perturbed in brain samples from humans with Alzheimer’s disease and frontotemporal dementia (FTD). Based on their findings in human patients and mice, the research team is proposing LSD1 as a central player in these neurodegenerative diseases and a drug target.

David Katz, PhD

The results were published Oct. 9 in Nature Communications.

In the brain, LSD1 (lysine specific histone demethylase 1) maintains silence among genes that are supposed to be turned off. When the researchers engineered mice that have the LSD1 gene snipped out in adulthood, the mice became cognitively impaired and paralyzed. Plenty of neurons were dying in the brains of LSD1-deleted mice, although other organs seemed fine. However, they lacked aggregated proteins in their brains, like those thought to drive Alzheimer’s disease and FTD.

“In these mice, we are skipping the aggregated proteins, which are usually thought of as the triggers of dementia, and going straight to the downstream effects,” says David Katz, PhD, assistant professor of cell biology at Emory University School of Medicine. Read more

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Tug of war between Parkinson’s protein and growth factors

Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.

The results were published this week in PNAS.

The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.

Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.

In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB.  [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]

A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more

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Imaging sleep drunkenness: #IHAW2017

At some point, everyone has experienced a temporary groggy feeling after waking up called sleep inertia. Scientists know a lot about sleep inertia already, including how it impairs cognitive and motor abilities, and how it varies with the time of day and type of sleep that precedes it. They even have pictures of how the brain wakes up piece by piece.

People with idiopathic hypersomnia or IH display something that seems stronger, termed “sleep drunkenness,” which can last for hours. Czech neurologist Bedrich Roth, the first to identify IH as something separate from other sleep disorders, proposed sleep drunkenness as IH’s defining characteristic.

Note: Emory readers may recall the young Atlanta lawyer treated for IH by David Rye, Kathy Parker and colleagues several years ago. Our post today is part of IH Awareness Week® 2017.

Sleep drunkenness is what makes IH distinctive in comparison to narcolepsy, especially narcolepsy with cataplexy, whose sufferers tend to fall asleep quickly. Those with full body cataplexy can collapse on the floor in response to emotions such as surprise or amusement. In contrast, people with IH tend not to doze off so suddenly, but they do identify with the statement “Waking up is the hardest thing I do all day.”

At Emory, neurologist Lynn Marie Trotti and colleagues are in the middle of a brain imaging study looking at sleep drunkenness.

“We want to find out if sleep drunkenness in IH is the same as what happens to healthy people with sleep inertia and is more pronounced, or whether it’s something different,” Trotti says. Read more

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Enhancing the brain’s clean up crews

Enhancing the brain’s own clean-up crews could be a strategy for handling the toxic proteins driving several neurodegenerative diseases, new research suggests.

Astrocytes, an abundant supportive cell type in the brain, are better than neurons at disposing of mutant huntingtin, the toxic protein that drives Huntington’s disease pathology, Xiao-Jiang Li and colleagues report in this week’s PNAS.

One reason why astrocytes are better at toxic protein defense than neurons is: they have less of an inhibitory protein called HspBP1. The scientists show that using CRISPR/Cas9 to “knock down” HspBP1 can help neurons get rid of mutant huntingtin and reduce early pathological signs.

Read more

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Granulins treasure not trash – potential FTD treatment strategy

Emory University School of Medicine researchers have developed tools that enable them to detect small proteins called granulins for the first time inside cells. Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously unclear.

FTD is an incurable neurodegenerative disease and the most common type of dementia in people younger than 60. Genetic variants in the granulin gene are also a risk factor for Alzheimer’s disease and Parkinson’s disease, suggesting this discovery may have therapeutic potential for a broad spectrum of age-related neurodegenerative diseases.

The results were published August 9 by the journal eNeuro (open access).

Thomas Kukar, PhD

Some neuroscientists believed that granulins were made outside cells, and even could be toxic under certain conditions. But with the newly identified tools, the Emory researchers can now see granulins inside cells within lysosomes, which are critical garbage disposal and recycling centers. The researchers now propose that granulins have important jobs in the lysosome that are necessary to maintain brain health, suppress neuroinflammation, and prevent neurodegeneration.

Problems with lysosomes appear in several neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

“A lysosomal function for granulins is exciting and novel.  We believe it may provide an explanation why decreased levels of granulins are linked to multiple neurodegenerative diseases, ranging from frontotemporal dementia to Alzheimer’s,” says senior author Thomas Kukar, PhD, assistant professor of pharmacology and neurology and the Emory University Center for Neurodegenerative Disease. Read more

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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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Drug discovery: selective anti-inflammatory approach to AD

Anyone familiar with Alzheimer’s disease research can say what a challenge drug development has been. In Emory’s Department of Pharmacology, Thota Ganesh is focusing on an anti-inflammatory approach. Ganesh’s work has been supported by the Alzheimer’s Drug Discovery Foundation and more recently by a five-year, $3.6 million grant from the National Institute on Aging.

Medicinal chemist Thota Ganesh, PhD, is focusing on an anti-inflammatory approach to Alzheimer’s disease, targeting the prostaglandin receptor EP2.

An assistant professor at Emory since 2011, he is continuing research he undertook with Ray Dingledine on EP2 antagonists. In animals, they showed that this class of compounds could reduce injury to the brain after a prolonged seizure. Since then, they have shown that EP2 antagonists have similar effects in protecting against organophosphate pesticides/nerve agents.

EP2 is one of the four receptors for prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Before Ganesh and colleagues from the Emory Chemical Biology Discovery Center started looking for them, chemicals that could block EP2 selectively were not available.

Their idea is: blocking EP2 is a better strategy than the more general approach of going after prostaglandins, the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and celecoxib (Celebrex). Read more

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