Mysterious DNA modification important in fly brain

Drosophila, despite being a useful genetic model of development, have very little DNA methylation on C. What they do have is methylation on A (technically, N6-methyladenine), although little was known about what this modification did for Read more

Where it hurts matters in the gut

What part of the intestine is problematic matters more than inflammatory bowel disease subtype (Crohn’s vs ulcerative colitis), when it comes to genetic activity signatures in pediatric Read more

Overcoming cisplatin resistance

Cisplatin was known to damage DNA and to unleash reactive oxygen species, but the interaction between cisplatin and Mek1/cRaf had not been observed Read more

Neuro

Huntington disease roundup

A lot is happening in the Huntington’s disease (HD) field right now. Emory research reports on a pig HD model and on CRISPR/Cas9 gene editing are just part of the wave.

Let’s step back and review the technologies now available to treat this neurodegenerative disease, caused by a gene producing a toxic protein. Antisense approaches, under development for decades and now in clinical trials, shut off the problematic gene. However, this type of treatment would need to be regularly delivered to nervous system tissues. Gene editing — not in the clinic yet — could actually remove the gene from somatic cells in affected individuals.

Emory researchers developed the pig HD model in collaboration with colleagues in Guangzhou, and anticipate it will be a practical way to test treatments such as gene editing. In comparison with mice, delivery to affected nervous system tissues can be better tested in pigs, because their size is closer to that of humans. The pig model of HD, published yesterday in Cell, also more closely matches the symptoms of the human disease. This research was covered by Chinese media organizations.

Also notable:

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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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Toe in the water for Emory cryo-EM structures

Congratulations to Christine Dunham and colleagues in the Department of Biochemistry for their first cryo-electron microscopy paper, recently published in the journal Structure.

The paper solves the structure of a bacterial ribosome bound to a messenger RNA containing a loop that regulates translation. This process is important for the study of several neurological diseases such as fragile X syndrome, for example.

Christine Dunham, PhD

Dunham writes: “We are focusing on establishing this in bacteria to understand frameshifting and protein folding as a consequence of codon preference. We will then build up our knowledge to potentially study eukaryotic translational control.”

The paper neatly links up with two Nobel Prizes: the 2017 Chemistry prize for cryo-electron microscopy and the 2009 Chemistry prize for ribosome structure, awarded in part to Dunham’s mentor Venki Ramakrishnan. Also, see this 2015 feature from Nature’s Ewen Callaway outlining how cryo-EM is a must have for structural biologists wanting to probe large molecules that are difficult to crystallize.

Construction now underway in the Biochemistry Connector will allow installation of microscopes (worth $6 million) necessary for Dunham and others to do cryo-EM here at Emory, although she advises that it will be several months until they are photo-op ready. For the Structure paper, Dunham collaborated with George Skiniotis at University of Michigan; he recently moved to Stanford. Read more

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Give a zap to Emory brain research for #STATMadness

Next week, we will be asking the Emory research community to support Emory’s entry in a contest. It’s like “Battle of the Bands.” Whoever gets the loudest cheers wins. We have some intriguing neuroscience research. Please help!

STAT Madness is a “March Madness” style bracket competition, but with biomedical research advances as competitors. Universities or research institutes nominate their champions, research that was published the previous year.

Our entry for 2018:

Direct amygdala stimulation can enhance human memory

The findings, from Cory Inman, Jon Willie and colleagues from the Department of Neurosurgery and Joe Manns from Psychology, were the first published example of electrical brain stimulation in humans giving an event-specific boost to memory lasting overnight. The research was conducted with epilepsy patients undergoing an invasive procedure for seizure diagnosis. However, the technology could one day be incorporated into a device aimed at helping those with memory impairments, such as people with traumatic brain injury or neurodegenerative diseases.

Extra note: you may have seen similar neuroscience research in a recent Nature Communications paper, which was described in the New York Times. Cory Inman had some comments below — he and neurosurgeon Robert Gross were co-authors:

The localization to the left lateral temporal cortex was interesting, because it hadn’t been identified as a region that modulates episodic or hippocampus-dependent memory. [The Emory authors stimulated the amygdala.] The more recent paper found a similar size of memory enhancement, with a slightly different and harder memory task of free recall, using “closed-loop” stimulation based on whether the brain is in a ‘bad’ encoding state. It’s possible that closed-loop stimulation could be used with the amygdala as well. 

Emory’s first opponoent is University of California, San Francisco. We are about half way down on the right side of the bracket.

As far as voting, you can fill out a whole bracket or you can just vote for Emory, along with other places you may feel an allegiance to. The contest will go several rounds. The first round begins on February 26. If Emory advances, then people will be able to continue voting for us starting March 2.

At the moment, you can sign up to be reminded to vote with an email address at:
https://signup.statnews.com/stat-madness

Starting Monday, February 26, you can follow the 2018 STAT Madness bracket and vote here:
https://www.statnews.com/feature/stat-madness/bracket/

Please share on social media using the hashtag #statmadness2018.

STAT is a life sciences-focused news site, launched in 2015 by the owner of the Boston Globe. It covers medical research and biotech nationally and internationally. Emory took part in 2017’s contest, with Tab Ansari’s groundbreaking work on SIV remission, a collaboration with Tony Fauci’s lab at NIAID.

 

 

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Viral vectors ready for delivery

The phrase “viral vector” sounds ominous, like something from a movie about spies and internet intrigue. It refers to a practical delivery system for the gene of your choice. If you are a biomedical researcher and you want to tweak genes in a particular part of the body in an experimental animal, viral vectors are the way to go.

Viral vector-transduced retinal ganglion cell; dendrites and axons labeled with GFP. Courtesy Felix Struebling via Xinping Huang

Emory’s Viral Vector Core was started when eminent neuroscientist Kerry Ressler was at Emory and is now overseen by geneticist Peng Jin. Technical director Xinping Huang and her colleagues can produce high-titer viral vectors, lentivirus and AAV. Discuss with her the best choice. It may depend on the size of the genetic payload you want to deliver and whether you want the gene to integrate into the genome of the target cell.

As gene therapy and CRISPR/Cas9-style gene editing research progresses, we can anticipate demand for services such as those provided by the Viral Vector Core. [Clinical applications are close, but will not be dealt with in the same place!]

Shi-Hua Li’s and Xiao-Jiang Li’s paper on CRISPR/Cas9 gene editing in a mouse model of Huntington’s disease, featured by NBC News last year, credits the Viral Vector Core. Read more

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Sifting proteomes for copper nuggets

Just because scientists know the gene responsible for a rare disease doesn’t mean they know what’s going on. NGLY1 is a good example. A handful of children around the world have an inherited deficiency in NGLY1, leading to a complex neurodevelopmental disorder. A family diagnosed at Emory thought their older affected daughter had cerebral palsy for most of her childhood. How the loss of an enzyme that removes sugar tags from certain proteins causes problems is still being uncovered.

More broadly, geneticists can read a family’s DNA sequences and find the differences, but figuring out what they mean is still a challenge. That’s where the approach taken in a recent paper in Cell Systems, by Emory cell biologist Victor Faundez and colleagues at Illinois State, comes in.

His lab used a comparison of proteomes to dissect Menkes disease, a rare inherited deficiency in a copper transport enzyme called ATP7A. This means they didn’t compare genes; instead, they compared the proteins produced by patients’ cells with those in their unaffected relatives.

Copper is an essential part of the diet and can be found at the active sites of several enzymes. The symptoms of Menkes disease arise because of a lack of copper in the body, although cultured cells lacking ATP7A actually accumulate copper. Read more

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Navigating monstrous anticancer obstacles

A new PNAS paper from geneticist Tamara Caspary’s lab identifies a possible drug target in medulloblastoma, the most common pediatric brain tumor. Come aboard to understand the obstacles this research seeks to navigate. Emory library link here.

Standard treatment for children with medulloblastoma consists of surgery in combination with radiation and chemotherapy. Alternatives are needed, because survivors can experience side effects such as neurocognitive impairment. One possibility has emerged in the last decade: inhibitors of the Hedgehog pathway, whose aberrant activation drives growth in medulloblastoma.

Medulloblastoma patients are caught “between Scylla and Charybdis”: facing a deadly disease, the side effects of radiation and/or existing Hedgehog inhibitors. From Wikimedia.

As this 2017 Oncotarget paper from St. Jude’s describes, Hedgehog inhibitors are no fun either. In adults, these agents cause muscle spasms, hair loss, distorted sense of taste, fatigue, and weight loss. In a pediatric clinical trial, the St. Jude group observed growth plate fusions, resulting in short stature. The drug described in the paper was approved in 2012 for basal cell carcinoma, a form of cancer whose growth is also driven by the Hedgehog pathway. Basal cell carcinoma is actually the most common form of human cancer, although it is often caught at an early stage that doesn’t require harsh treatment.

Caspary’s lab studies the Hedgehog pathway in early embryonic development. In the PNAS paper, former graduate student Sarah Bay and postdoc Alyssa Long show that targeting a downstream part of the Hedgehog pathway may be a way to avoid problems presented by both radiation/chemo and existing Hedgehog inhibitors. 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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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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