Neuroscience
Month
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).
The study was published online ahead of print on November 8, 2012, by the journal Structure.
The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration.
"Our findings have long-range implications for drug discovery," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate competitive inhibitors for this enzyme with even greater specificity and hopefully less toxicity."
The scientists used what they called structure class analysis, looking at groups of structures, which revealed subtle differences not apparent looking at them individually.
"From a structural point of view, these different proteins appear to be very similar, but the biochemistry shows that the results of their binding to JNK were very different," he said.
LoGrasso and his colleagues were responsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis.
All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell’s fate.
"Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them."
Sanford-Burnham researchers discovered that the protein appoptosin prompts neurons to commit suicide in several neurological conditions—giving them a new therapeutic target for Alzheimer’s disease and traumatic brain injury.
Dying neurons lead to cognitive impairment and memory loss in patients with neurodegenerative disorders–conditions like Alzheimer’s disease and traumatic brain injury. To better diagnose and treat these neurological conditions, scientists first need to better understand the underlying causes of neuronal death.
Enter Huaxi Xu, Ph.D., professor in Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center. He and his team have been studying the protein appoptosin and its role in neurodegenerative disorders for the past several years. Appoptosin levels in the brain skyrocket in conditions like Alzheimer’s and stroke, and especially following traumatic brain injury.
Appoptosin is known for its role in helping the body make heme, the molecule that carries iron in our blood (think “hemoglobin,” which makes blood red). But what does heme have to do with dying brain cells? As Xu and his group explain in a paper they published recently in the Journal of Neuroscience, excess heme leads to the overproduction of reactive oxygen species, which include cell-damaging free radicals and peroxides, and triggers apoptosis, the carefully regulated process of cellular suicide. This means that more appoptosin and more heme cause neurons to die.
Not only did Xu and his team unravel this whole appoptosin-heme-neurodegeneration mechanism, but when they inhibited appoptosin in laboratory cell cultures, they noticed that the cells didn’t die. This finding suggests that appoptosin might make an interesting new therapeutic target for neurodegenerative disorders.
What’s next? Xu and colleagues are now probing appoptosin’s function in mouse models. They’re also looking for new therapies that target the protein.
“Since the upregulation of appoptosin is important for cell death in diseases such as Alzheimer’s, we’re now searching for small molecules that modulate appoptosin expression or activity. We’ll then determine whether these compounds may be potential drugs for Alzheimer’s or other neurodegenerative diseases,” Xu explains.
Putting a stop to runaway appoptosin won’t be easy, though. That’s because we still need the heme-building protein to operate at normal levels for our blood to carry iron. In a previous study, researchers found that a mutation in the gene that encodes appoptosin causes anemia. “Too much of anything is bad, but so is too little,” Xu says.
New therapies that target neurodegenerative disorders and traumatic brain injury are sorely needed. According to the CDC, approximately 1.7 million people sustain a traumatic brain injury each year. It’s an acute injury, but one that can also lead to long-term problems, causing epilepsy and increasing a person’s risk for Alzheimer’s and Parkinson’s diseases. Not only has traumatic brain injury become a worrisome problem in youth and professional sports in recent years, the Department of Defense calls traumatic brain injury “one of the signature injuries of troops wounded in Afghanistan and Iraq.”
Researchers supported by the Wellcome Trust have discovered that we use a different part of our brain to learn about social hierarchies than we do to learn ordinary information. The study provides clues as to how this information is stored in memory and also reveals that you can tell a lot about how good somebody is likely to be at judging social rank by looking at the structure of their brain.
Primates (and people) are remarkably good at ranking each other within social hierarchies, a survival technique that helps us to avoid conflict and select advantageous allies. However, we know surprisingly little about how the brain does this.
The team at the UCL Institute for Cognitive Neuroscience used brain imaging techniques to investigate this in twenty six healthy volunteers.
Participants were asked to play a simple science fiction computer game where they would be acting as future investors. In the first phase they were told they would first need to learn about which individuals have more power within a fictitious space mining company (the social hierarchy), and then which galaxies have more precious minerals (non-social information).
Whilst they were taking part in the experiments, the team used functional magnetic resonance imaging (fMRI) to monitor activity in their brains. Another MRI scan was also taken to look at their brain structure.
Their findings reveal a striking dissociation between the neural circuits used to learn social and non-social hierarchies. They observed increased neural activity in both the amygdala and the hippocampus when participants were learning about the hierarchy of executives within the fictitious space mining company. In contrast, when learning about the non-social hierarchy, relating to which galaxies had more mineral, only the hippocampus was recruited.
There’s no question that our ability to remember informs our sense of self. Now research published in Clinical Psychological Science, a journal of the Association for Psychological Science, provides new evidence that the relationship may also work the other way around: Invoking our sense of self can influence what we are able to remember.
Research has shown that self-imagination – imagining something from a personal perspective – can be an effective strategy for helping us to recognize something we’ve seen before or retrieve specific information on cue. And these beneficial effects have been demonstrated for both healthy adults and for individuals who suffer memory impairments as a result of brain injury.
These findings suggest that self-imagination is a promising strategy for memory rehabilitation. But no study has investigated the effect of self-imagination on what is perhaps the most difficult, and most relevant, type of memory: free recall.
Targeted light transmission to genetically altered brain cells stops seizures cold.
Strobe lights can trigger epileptic seizures. Now imagine a light that stops a seizure a split second after it starts.
By applying pulses of light to genetically altered nerve cells deep in rat brains, researchers at Stanford and Pierre and Marie Curie University in France have done just that. Their results, which showed for the first time how a part of the brain called the thalamus is involved with epileptic seizures, were published in Nature Neuroscience.
The study could point toward new targets for epilepsy treatment, says Ed Boyden, associate professor and leader of the Synthetic Biology Group at MIT. Boyden was not involved in the work. Some ideas “might emerge immediately from knowing new targets to insert deep brain stimulation electrodes,” a type of device already used to help people with epilepsy, Boyden says.
The latest research looked at a kind of seizure that sometimes follows damage to the cerebral cortex, the outer part of the brain, from strokes or head injuries. Previous reports had hinted that the cortex might also communicate during a seizure with the thalamus, the brain’s message relay center.
In the current study, experiments with rats confirmed that the thalamus propagates seizure activity originating in the cortex. To see if the thalamus could be a target for treating seizures, Jeanne Paz, the paper’s lead author, and her colleagues turned to optogenetics, a technology that lets researchers use light to turn brain cells on and off.
For the “genetics” part, they used a virus to insert the DNA code for a light-sensitive protein into thalamus cells of rats. When exposed to light, the protein interferes with these cells’ ability to communicate.
The researchers then developed a light source that would turn on only when a rat had a seizure. To detect seizures, they implanted electrodes into the rats’ brains. When these electrodes registered a seizure starting, light from a laser was aimed directly at the genetically altered thalamus cells. The result, the researchers found, was that flipping on the light immediately stopped the seizure activity, proving that the thalamus is needed to keep seizures going.
“We’re excited that just a brief light exposure was enough to stop the seizure,” says John Huguenard, Stanford professor of neurology and neurological sciences and an author of the study.
However, Huguenard says, an optogenetics-based brain implant to control seizures is a long way off because of the unknown risks of altering a person’s DNA with a virus. “I would want to be cautious,” he says.
UC Irvine researchers have created a new stem cell-derived cell type with unique promise for treating neurodegenerative diseases such as Alzheimer’s.
Dr. Edwin Monuki of UCI’s Sue & Bill Gross Stem Cell Research Center, developmental & cell biology graduate student Momoko Watanabe and colleagues developed these cells — called choroid plexus epithelial cells — from existing mouse and human embryonic stem cell lines.
CPECs are critical for proper functioning of the choroid plexus, the tissue in the brain that produces cerebrospinal fluid. Among their various roles, CPECs make CSF and remove metabolic waste and foreign substances from the fluid and brain.
In neurodegenerative diseases, the choroid plexus and CPECs age prematurely, resulting in reduced CSF formation and decreased ability to flush out such debris as the plaque-forming proteins that are a hallmark of Alzheimer’s. Transplant studies have provided proof of concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture.
“Our method is promising, because for the first time we can use stem cells to create large amounts of these epithelial cells, which could be utilized in different ways to treat neurodegenerative diseases,” said Monuki, an associate professor of pathology & laboratory medicine and developmental & cell biology at UCI.
The study appears in The Journal of Neuroscience
To create the new cells, Monuki and his colleagues coaxed embryonic stem cells to differentiate into immature neural stem cells. They then developed the immature cells into CPECs capable of being delivered to a patient’s choroid plexus.
These cells could be part of neurodegenerative disease treatments in at least three ways, Monuki said. First, they’re able to increase the production of CSF to help flush out plaque-causing proteins from brain tissue and limit disease progression. Second, CPEC “superpumps” could be designed to transport high levels of therapeutic compounds to the CSF, brain and spinal cord. Third, these cells can be used to screen and optimize drugs that improve choroid plexus function.
Monuki said the next steps are to develop an effective drug screening system and to conduct proof-of-concept studies to see how these CPECs affect the brain in mouse models of Huntington’s, Alzheimer’s and pediatric diseases.
When it comes to Alzheimer’s disease, scientists usually — and understandably — look to the brain as their first center of attention. Now researchers at Tel Aviv University say that early clues regarding the progression of the disease can be found in the brain’s metabolism.
In very early stages of the disease, before any symptoms appear, metabolic processes are already beginning to change in the brain, says PhD candidate Shiri Stempler of TAU’s Sackler Faculty of Medicine. Working with Profs. Eytan Ruppin and Lior Wolf of TAU’s Blavatnik School of Computer Science, Stempler has developed predictor models that use metabolic information to pinpoint the progression of Alzheimer’s. These models were 90 percent accurate in predicting the stage of the disease.
Published in the journal Neurobiology of Aging, the research is the first step towards identifying biomarkers that may ensure better detection and analysis of the disease at an early stage, all with a simple blood test. It could also lead to novel therapies. “We hope that by studying metabolism, and the alterations to metabolism that occur in the very early stages of the disease, we can find new therapeutic strategies,” adds Stempler.
Every week in his clinic at the University of Michigan, neurologist Joseph Corey, M.D., Ph.D., treats patients whose nerves are dying or shrinking due to disease or injury.
He sees the pain, the loss of ability and the other effects that nerve-destroying conditions cause – and wishes he could give patients more effective treatments than what’s available, or regenerate their nerves. Then he heads to his research lab at the VA Ann Arbor Healthcare System, where his team is working toward that exact goal.
In new research published in several recent papers (Nature Methods, Biomacromolecules, Materials Science and Engineering) Corey and his colleagues from the U-M Medical School, VAAAHS and the University of California, San Francisco report success in developing polymer nanofiber technologies for understanding how nerves form, why they don’t reconnect after injury, and what can be done to prevent or slow damage.
Using polymer nanofibers thinner than human hairs as scaffolds, researchers coaxed a particular type of brain cell to wrap around fibers that mimic the shape and size of nerves found in the body.
They’ve even managed to encourage the process of myelination – the formation of a protective coating that guards larger nerve fibers from damage. They began to see multiple concentric layers of the protective substance called myelin start to form, just as they do in the body.
Humans share over 90% of their DNA with their primate cousins. The expression or activity patterns of genes differ across species in ways that help explain each species’ distinct biology and behavior.
DNA factors that contribute to the differences were described on Nov. 6 at the American Society of Human Genetics 2012 meeting in a presentation by Yoav Gilad, Ph.D., associate professor of human genetics at the University of Chicago.
Dr. Gilad reported that up to 40% of the differences in the expression or activity patterns of genes between humans, chimpanzees and rhesus monkeys can be explained by regulatory mechanisms that determine whether and how a gene’s recipe for a protein is transcribed to the RNA molecule that carries the recipe instructions to the sites in cells where proteins are manufactured.
In addition to improving scientific understanding of the uniqueness of humans, studies such as the investigation conducted by Dr. Gilad and colleagues could have relevance to human health and disease.
"Through inter-species’ comparisons at the DNA sequence and expression levels, we hope to identify the genetic basis of human specific traits and in particular the genetic variations underlying the higher susceptibility to certain diseases such as malaria and cancer in humans than in non-human primates," said Dr. Gilad.
Dr. Gilad and his colleagues studied gene expression in lymphoblastoid cell lines, laboratory cultures of immortalized white blood cells, from eight humans, eight chimpanzees and eight rhesus monkeys.
They found that the distinct gene expression patterns of the three species can be explained by corresponding changes in genetic and epigenetic regulatory mechanisms that determine when and how a gene’s DNA code is transcribed to a messenger RNA (mRNA) molecule.
Dr. Gilad also determined that the epigenetics process known as histone modification also differs in the three species. The presence of histone marks during gene transcription indicates that the process is being prevented or modified.
"These data allowed us to identify both conserved and species-specific enhancer and repressor regulatory elements, as well as characterize similarities and differences across species in transcription factor binding to these regulatory elements," Dr. Gilad said.
Among the similarities among the three species were the promoter regions of DNA that initiated transcription of a particular gene.
In all three species, Dr. Gilad’s lab found that transcription factor binding and histone modifications were identical in over 67% of regulatory elements in DNA segments that are regarded as promoter regions.
The researchers presentation is titled, “Genome-wide comparison of genetic and epigenetic regulatory mechanisms in primates.”