Transgenic Huntington’s disease monkeys display a full spectrum of symptoms resembling the human disease, ranging from motor problems and neurodegeneration to emotional dysregulation and immune system changes, scientists at Yerkes National Primate Research Center, Emory University report.
The results, published online in the journal Brain, Behavior and Immunity, strengthen the case that transgenic Huntington’s disease monkeys could be used to evaluate emerging treatments (such as this) before launching human clinical trials.
“Identifying emotional and immune symptoms in the HD monkeys, along with previous studies demonstrating their cognitive deficits and fine motor problems, suggest the HD monkey model embodies the full array of symptoms similar to human patients with the disease,” says Yerkes research associate Jessica Raper, PhD, lead author of the paper. Read more
It’s sweet, it’s safe, and it looks like it could save neurons. What is it? Trehalose.
Trehalose is a natural sugar.
This natural sugar is used in the food industry as a preservative and flavor enhancer (it’s in Taco Bell’s meat filling). And curiously, medical researchers keep running into trehalose when they’re looking for ways to fight neurodegenerative diseases.
A recent example from Emory’s Department of Pharmacology: Chris Holler, Thomas Kukar and colleagues were looking for drugs that might boost human cells’ production of progranulin (PGRN), a growth factor that keeps neurons healthy. Mutations in the progranulin gene are a common cause of frontotemporal dementia.
The Emory scientists discovered two leads: a class of compounds called mTOR inhibitors — the transplant drug rapamycin is one — and trehalose. The team decided to concentrate on trehalose because it increased PGRN levels in neuronal and non-neuronal cell types, unlike the mTOR inhibitors. Their results were published at the end of June in Molecular Neurodegeneration.
The team confirmed their findings by examining the effects of trehalose on cells derived from patients with progranulin mutations. This paper is the first to include results from Emory’s Laboratory of Translational Cell Biology, which was established in 2012 to facilitate this type of “disease in a dish” approach. Cell biologists Charles Easley, Wilfried Rossoll and Gary Bassell from the LTCB, and neurologists Chad Hales and William Hu from the Center for Neurodegenerative Disease are co-authors.
Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.
Scientists showedÂ that by manipulating a particular growth factor in one region of the brain, they couldÂ tune up or down a mouseâ€™s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.
â€œWhen we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,â€ says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. â€œWe think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.â€
The results were published WednesdayÂ inÂ Journal of Neuroscience.
Shannon Gourley, PhD
Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.
The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.
Emory’s Alzheimer’s Disease Research Center recently announced a grant that will support studies on the connections between blood pressure regulation and Alzheimer’s disease. It focuses on the roles of the renin-angiotensin system, the targets of common blood pressure medications, and endothelial cells, which line blood vessels.
Research on that theme is already underway at Emory. Malu Tansey is leading a large project funded by the National Institute on Aging ($3.4 million) with a similar title: “Inflammation and Renin-Angiotensin System Dysfunction as Risk Factors for Alzheimer’s Disease.” Co-investigators are Felicia Goldstein and Lary Walker at Emory and Christopher Norris at the University of Kentucky.
Both studies build on evidence that molecules that control blood pressure and inflammation also drive progression of Alzheimer’s disease, including work by Emory’s Whitney Wharton and Ihab Hajjar. They had found in an observational study that people who take medications targeting the renin-angiotensin system have a lower risk of progressing from mild cognitive impairment to Alzheimer’s.
Wharton is gearing up to test that idea more directly in an interventional study with the generic angiotensin receptor blocker telmisartan. This study is part of a Part the Cloud initiative supported by the Alzheimer’s Association.
Tansey’s project has started bearing fruit in an animal model of Alzheimer’s, according to this Keystone meeting report from Alzforum. Last summer, her graduate student Kathryn Macpherson described initial findings on the effects of an anti-inflammatory (anti-TNF) agent, which also has positive effects in a Parkinson’s model, and her plans to investigate the effects of high-sugar, high-fat diet.
Emory researchers were part of a recent advance in understanding how the Zika virus harms the developing brain. The research was published March 4 inÂ Cell Stem Cell.Â
Emory geneticist Peng Jin and his colleagues were part of a rapidly assembled research team, including scientists from Johns Hopkins and Florida State University, that showed the Zika virus can infect neural progenitor cells critical for brain development.
The research suggests a potential explanation for the cases of microcephaly seen in Latin America during the Zika outbreak. While it does not prove the direct link between Zika and microcephaly, it is a first step that shows where the virus may be doing the most damage.
The team showed that the Zika virus infects a type of neural stem cell that gives rise to the brainâ€™s cerebral cortex. The researchers used neural progenitor cells, formed from induced pluripotent stem cells (iPSCs). The scientists showed that the virus infects neural progenitor cells more readily than iPSCs or immature neurons.
Zhexing Wen, PhD
The role of Jin’s lab was to analyze how the patterns of gene activity in neuronal cells were altered by Zika infection. Jin reports the team is continuing to examine the differences between the effects of Zika and other related viruses such as dengue and West Nile.
In addition, Lab Land recently learned that one of the scientists from Johns Hopkins, Zhexing Wen, was recruited to Emory as faculty and will start in June. His research won’t be all about Zika — in Guo-li Ming’s lab, Wen gained experience using iPSCs to model complex brain disorders such as schizophrenia. Read more
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