Adult mice don’t need the gene that, when mutated in humans, causes the inherited neurodegenerative disorder Huntington’s disease.Â The finding suggests that treatment strategies for Huntington’s that aim to shut off the huntingtin gene in adults — now in early clinical stages — could be safe.
The results were publishedÂ Monday, March 7 inÂ PNAS.
How HD gene silencing is supposed to work. The Emory study didn’t test this approach directly, but the Emory studyÂ has implications for what types of side effects HD gene silencingÂ may have in humans. Image from HDBuzz.net via Creative Commons.
Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline. A juvenile form of Huntington’s disease also can appear during the teenage years.
Researchers led by Xiao-Jiang Li, MD, PhD and Shihua Li, MD, at Emory University School of Medicine, used genetically engineered mice in which the huntingtin gene can be deleted, triggered only when the mice are given the drug tamoxifen. Note: these mice don’t produce toxic mutant huntingtin protein.
When the huntingtin gene is deleted at an age older than four months, these mice appeared to stay healthy, despite having lost their huntingtin genes in cells all over their bodies. They maintained their body weight and could complete tests of movement and grip strength as well as control mice.Â In contrast with adults, engineered mice younger than four months old whose huntingtin gene was deleted developed lethal pancreatitis.
Don’t call them alternative careers — since most graduate students in the biomedical sciences won’t end up as professors. Since I found a career outside the laboratory myself, I like to keep an eye out for examples of Emory people who have made a similar jump. [Several more in this Emory Magazine feature, which mentions the BEST program, aimed at facilitating that leap.]
Debra Cooper, PhD
After a postdoc in Texas, former Emory neuroscience graduate student Debra Cooper was awarded a California Council on Science and Technology fellowship to work with the California State Senate staff, and is now a policy consultant there. More about her work can also be found at the CCST blog.
Describe your position as policy consultant now. What types of things do you work on? How does your experience in neuroscience/drug abuse research fit in?
As a policy consultant at the California State Senate Office of Research, I function as a bridge between policy and the technical information that informs public policy. A large component of my time is spent translating research and linking it with relevant policies and regulations. I then synthesize this information and disseminate it to the appropriate audiences through memoranda, reports, or presentations. Sometimes this information is used to advise and make recommendations for legislative ideas.
My main assignments deal with human services (i.e., public services provided by governmental organizations) and veterans affairs. As such, not every project that I work on is directly related to neuroscience, but I often find overlap between my assignments and my academic background. For instance, the intersection of mental health and veterans affairs services is an important topic that bridges my backgrounds. Even when Iâ€™m working on issues that donâ€™t directly link to mental health, the years that I spent analyzing research and statistics comes in handy when evaluating relevant documents.
Describe your graduate research at Emory.
I had co-advisors while working on my PhD at Emory â€“ Drs. David Weinshenker and Leonard Howell. My dissertation research focused on one question answered with two different model animals: rats (Weinshenker lab) and squirrel monkeys (Howell lab). I was studying the effectiveness of a drug, nepicastat, in reducing rates of relapse to cocaine abuse. Nepicastat blocks an enzyme (dopamine beta-hydoxylase) which is crucial for converting the neurochemical dopamine into the neurochemical norepinephrine. Both of these neurochemicals are involved in responses to cocaine, and we hypothesized that nepicastat could help in regulating these neurochemicals to prevent relapse. Read more
In ancient Greek mythology, the souls of the dead were made to drink from the river Lethe, so that they would forget their past lives. Something analogous happens to genes at the very beginning of life. Right after fertilization, the embryo instructs them to forget what it was like in the egg or sperm where they had come from.
This is part of the “maternal-to-zygote transition”: much of the epigenetic information carried on and around the DNA is wiped clean, so that the embryo can start from a clean slate.
Developmental biologist Lewis Wolpert once said: “It is not birth, marriage or death which is
the most important time in your life, but gastrulation,” referring to when the early embryo separates into layers of cells that eventually make up all the organs. Well, the MZT, which occurs first, comes pretty close in importance.
When this process of epigenetic reprogramming is disrupted, the consequences are often lethal. Emory cell biologists David Katz and Jadiel Wasson discovered that when mouse eggs are missing an enzyme that is critical for the MZT, on the rare instances when the mice survive to adulthood, they display odd repetitive behaviors. Read more
Much of basic biomedical research concerns proteins. The enzymes that keep cells running, the regulators and receptors that control what our cells do, the antibodies that defend us against invaders — all of these are proteins.
That means every day, scientists are asking questions like:
What’s happening to my favorite protein? Is there more or less of it in this sample? What other proteins work with it or stick to it?
That’s where a proteomics core facility comes in. Given a mixture of hundreds or even thousands of proteins, proteomics specialists can separate, identify and quantify them.
Researchers in the areas of Alzheimer’s disease, cancer metabolism, schizophrenia and vaccines all make use of Emory’s proteomics core facility. It was key to the Alzheimer’s Disease Research Center’s 2013 discovery of a new form of Alzheimer’s disease protein pathology.
Director Nick Seyfried reports that the core has acquired close to $3 million in sophisticated mass spectrometry equipment in the last few years. The Emory Integrated Proteomics Core, one of the Emory Integrated Core Facilities, is supported in part by the Winship Cancer Institute, the Atlanta Clinical and Translational Science Institute, and a recently renewed grant for ENNCF (Emory Neurosciences NINDS Core Facilities).
Protein mass spectrometry is like Wonkavision
There’s a scene in both the 1971 and 2005 film adaptations of Roald Dahl’s Charlie and the Chocolate Factory, in which a chocolate bar is separated into millions of tiny pieces and sent flying across a clean room. Protein mass spectrometry resembles the first part of this process. Read more
Lab Land’s editor enjoyed talking with several students about their work at the GDBBS Student Research Symposium last week. Neurons dominateÂ the three contest-winning images. The Integrated Cellular Imaging coreÂ facilityÂ judged the winners. From left to right:
1st Place: Stephanie Pollitt,Â Neuroscience
2nd Place: Amanda York,Â Biochemistry, Cell and Developmental Biology
3rd Place: Jadiel Wasson, Biochemistry, Cell and Developmental Biology
Larger versions and explanations below.
Research on depression must deal with a major obstacle: the placebo effect. This is the observation that patients improve in response to the sugar pills given as controls in clinical studies.
Clinical trial designers can incorporate various clever strategies to minimize the placebo effect, which is actually comprised of severalÂ statistical and psychological factors. Investigators can try to enhance, dissect or even â€œharnessâ€ them. [A recent piece in the New York Times from Jo Marchant focuses on the placebo effect in studies of pain relief.]
Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.
Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Millerâ€™s team describes here (less guilt!), but they conclude that there is a â€œhigh degree of overlap.â€
Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitful investigations of inflammation in the context of major depression. More on that soon.
On Friday, NINDS director Walter Koroshetz made an interesting remark in a lecture to Emoryâ€™s Department of Neurology. He said that in the 2016 National Institues of Health budget, neuroscience is now the largest â€œbucket of money,â€ especially with the recent boost in funding for Alzheimerâ€™s research. Thatâ€™s larger than the bucket for cancer. To be sure, biomedical research in general got a boost from Congress, with the NIH receiving its largest increase in a decade, and cancer is still a big deal!
Koroshetz explained that neuroscience research is spread out among NINDS (National Institute for Neurological Disorders and Stroke), NIMH (National Institute of Mental Health), NIDA (National Institute for Drug Abuse) and several others, while cancer research is concentrated at the National Cancer Institute. [Hereâ€™s some official category tracking that the NIH does â€“ his breakdown checks out.]
Koroshetz highlighted a project from Dieter Jaeger and Garret Stanley that is part of the White Houseâ€™s BRAIN Initiative focused on mapping brain circuits and connectivity. He also noted NINDSâ€™s efforts in promoting translational research, since pharmaceutical companies were frustrated by repeated failures in the 1990s with difficult areas such as stroke, and the R35 mechanism for funding â€œoutstanding investigatorsâ€ for up to eight years continuously.
Violence and trauma are certainly not gifts, but scientifically, the Grady Trauma Project keeps on giving, even after co-director Kerry Resslerâ€™s 2015 move to Massachusetts. Research at Emory on the neurobiology of post-traumatic stress disorder (PTSD) continues. This Nature Communications paper, published in December with VA-based psychiatrist Aliza Wingo as lead author, is an example.
Three interesting things about this paper:
- The focus on PTSD co-occurring with depression. As the authors note, several studies looking at traumatized individuals found PTSD and depression together more often than they were present separately. This was true of Atlanta inner city residents in the Grady Trauma Project, veterans and survivors of the 2001 World Trade Center attack.
- DICER: the gene whose activity is turned down in blood samples from people with PTSD plus depression. Its name evokes one of the three Fates in Greek mythology, Atropos, who cuts the thread of life. DICER is at the center of a cellular network of regulation, because it is part of the machinery that generates regulatory micro-RNAs.
- The findings recapitulate work in mouse models of stress and its effects on the brain, with a connection to the many-tentacled Wnt signaling/adhesion protein beta-catenin.
Some past posts on the Grady Trauma Projectâ€™s scientific fruits follow. Read more
This summer, video producers from the web site LabTV came to two laboratories at Emory. We are pleased to highlightÂ the first crop of documentary-style videos.
LabTV features hundreds of young researchers from universities and institutes around the United States, who tell the public about themselves and their research. The videos include childhood photos and explanations from the scientists about what they do and what motivates them.Â
The two Emory labs are: Malu Tansey’s lab in the Department of Physiology, which studies the intersection of neuroscience and immunology, focusing on neurodegenerative disease, and Mike Davis’ lab in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, which is developing regenerative approaches and technologies for heartÂ disease in adults and children. Read more
Earlier today, weÂ posted a notice on Eurekalert for a Sunday, December 13 presentation by graduate student Jessica Konen at theÂ American Society for Cell Biology meeting in San Diego.
Her research, performed with Adam Marcus at Winship Cancer Institute, was the topic of a video that recently won first prize in a contest sponsored by the Association of American Medical Colleges. ThisÂ was our video team’s first use of theÂ “fast hand on whiteboard” effect, and a lot of fun to make. The video’s strength growsÂ out of the footageÂ Konen and Marcus have of cancer cells migrating in culture. Check it out, if you haven’t already.
PosterÂ presentations at the 2015 ASCB meeting can be found by searching this PDF. A few Emory-centric highlights:
*Chelsey Ruppersburg and Criss Hartzell’s work on the “nimbus”, a torus-shaped structure enriched in proteins needed to build the cell’s primary cilium
*Anita CorbettÂ on how Emory students have a strong record of attaining their own NIH research funding
*Additional work by Adam Marcus’ lab on the tumor suppressor gene LKB1 and how its loss drives lung cancer cells to take on a “unique amoeboid morphology”
*Research from David Katz’s lab on the “epigenetic eraser” LSD1 (lysine-specific demethylase) and its function in neurons and neurodegeneration Read more