By using a model, researchers at the University of Montreal have identified and “switched off” a chemical chain that causes neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis and dementia. The findings could one day be of particular therapeutic benefit to Huntington’s disease patients. “We’ve identified a new way to protect neurons that express mutant huntingtin proteins,” explained Dr. Alex Parker of the University of Montreal’s Department of Pathology and Cell Biology and its affiliated CRCHUM Research Centre. A cardinal feature of Huntington’s disease – a fatal genetic disease that typically affects patients in midlife and causes progressive death of specific areas of the brain – is the aggregation of mutant huntingtin protein in cells. “Our model revealed that increasing another cell chemical called progranulin reduced the death of neurons by combating the accumulation of the mutant proteins. Furthermore, this approach may protect against neurodegenerative diseases other than Huntington’s disease.”
There is no cure for Huntingdon’s disease and current strategies show only modest benefits, and a component of the protein aggregates involved are also present in other degenerative diseases. “My team and I wondered if the proteins in question, TDP-43 and FUS, were just innocent bystanders or if they affected the toxicity caused by mutant huntingtin,” Dr. Parker said. To answer this question, Dr. Parker and University of Montreal doctoral student Arnaud Tauffenberger turned to a simple genetic model based on the expression of mutant huntingtin in the nervous system of the transparent roundworm C. elegans. A large number of human disease genes are conserved in worms, and C. elegans in particular enables researchers to rapidly conduct genetic analyses that would not be possible in mammals.
Dr. Parker’s team found that deleting the TDP-43 and FUS genes, which produce the proteins of the same name, reduced neurodegeneration caused by mutant huntingtin. They then confirmed their findings in the cell of a mammal cell, again by using models. The next step was then to determining how neuroprotection works. TDP-43 targets a chemical called progranulin, a protein linked to dementia. “We demonstrated that removing progranulin from either worms or cells enhanced huntingtin toxicity, but increasing progranulin reduced cell death in mammalian neurons. This points towards progranulin as a potent neuroprotective agent against mutant huntingtin neurodegeneration,” Dr. Parker said. The researchers will need to do further testing this in more complex biological models to determine if the same chemical switches work in all mammals. If they do, then progranulin treatment may slow disease onset or progression in Huntington’s disease patients.
(Source: eurekalert.org)
Filed under brain neurodegenerative diseases ALS genetic model Huntington's disease huntingtin protein neuroscience science
Metabolic Protein Launches Sugar Feast That Nurtures Brain Tumors
Researchers at The University of Texas MD Anderson Cancer Center have tracked down a cancer-promoting protein’s pathway into the cell nucleus and discovered how, once there, it fires up a glucose metabolism pathway on which brain tumors thrive.
They also found a vital spot along the protein’s journey that can be attacked with a type of drug not yet deployed against glioblastoma multiforme, the most common and lethal form of brain cancer. Published online by Nature Cell Biology, the paper further illuminates the importance of pyruvate kinase M2 (PKM2) in cancer development and progression.
"PKM2 is very active during infancy, when you want rapid cell growth, and eventually it turns off. Tumor cells turn PKM2 back on - it’s overexpressed in many types of cancer," said Zhimin Lu, M.D., Ph.D., the paper’s senior author and an associate professor in MD Anderson’s Department of Neuro-Oncology.
Lu and colleagues showed earlier this year that PKM2 in the nucleus also activates a variety of genes involved in cell division. The latest paper shows how it triggers aerobic glycolysis, processing glucose into energy, also known as the Warburg effect, upon which many types of solid tumors rely to survive and grow.
"PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways. PKM2 could be an Achilles’ heel for cancer."
By pinpointing the complicated steps necessary for PKM2 to penetrate the nucleus, Lu and colleagues found a potentially druggable target that could keep the protein locked in the cell’s cytoplasm.
(Image Credit: Wikimedia Commons)
Filed under brain tumors PKM2 protein cancer glioblastoma glucose science
Some people live their lives by the motto “no risk - no fun!” and avoid hardly any risks. Others are clearly more cautious and focus primarily on safety when investing and for other business activities. Scientists from the University of Bonn in cooperation with colleagues from the University of Zurich studied the attitudes towards risk in a group of 56 subjects. They found that in people who preferred safety, certain regions of the brain show a higher level of activation when they are confronted with quite unforeseeable situations. In addition, they do not distinguish as clearly as risk takers whether a situation is more or less risky than expected. The results have just been published in the renowned “Journal of Neuroscience.”
"We were especially interested in the link between risk preferences and the brain regions processing this information," says Prof. Dr. Bernd Weber from the Center for Economics and Neuroscience (CENs) at the University of Bonn. First, the researchers tested a total of 56 subjects for their willingness to take risks. "In an economic game, the test subjects had a choice between a secured payout and a lottery," reports Sarah Rudorf from CENs, the study’s principal author. Those who showed a strong preference for the lottery in this test were categorized as risk takers. Others preferred the secured payout even if the lottery’s odds of winning were clearly better. They were put in the risk-averse group.
In risk-averse individuals, certain regions of the brain are activated more strongly
Then the test subjects played a card game in a brain scanner to study their risk perception. Cards carrying numbers from one to ten were shown on the video glasses in front of their eyes. Each time, two cards were randomly drawn. Before the subjects were shown the cards, they were asked to place bets on whether the second card would have a higher or a lower number than the first one. “The statistical probability for either case to occur is always the same: fifty-fifty,” says Prof. Weber. “This is important so that all subjects, whether they are risk takers or not, experience risky situations inside the scanner.” They were not able to assess their probability of winning their bet until they saw the first card. Here, the researchers found that in the subjects who tended to avoid risks, two specific regions of the brain were activated more strongly than in those who were willing to take risks. These areas are the ventral striatum and the insular cortex. The ventral striatum reacts both to the probability of winning, as well as to how well an individual can predict the outcome of the bet. The insular cortex is particularly sensitive to the risk a situation carries, and for whether it is higher or lower than anticipated.
Risk seekers adjust their strategy after lucky streaks
Sarah Rudorf summarized the results, “Individuals in whom these regions of the brain are activated at a higher level seem to perceive risks more clearly and assess them as more negative than those who are willing to take risks.” Risk-averse individuals seem to overestimate the con¬sequences of risk, and they did not distinguish as clearly between situations that turned out to be more or less risky than expected. In contrast, the test subjects who tended to take greater risks also focused their behavior more towards the wins and losses, and more clearly changed their strategy after negative situations.
Study is first to show the neurobiological mechanisms
"This study is the first to show the neurobiological mechanisms of how individual risk preferences determine risk perception," says Prof. Weber. "This also has effects on behavior in the areas of finance and health."
In a next step, the researchers want to study the consequences these results have on economic decisions such as in the stock market. “This might even allow improving the advising process for investors with regard to their individual risk behavior,” says Prof. Weber. And he considers health another important area. Smokers know that what they do is very dangerous, and yet they smoke. “If we learned more about smokers’ attitudes towards risk, we might be able to provide information for developing better anti-smoking campaigns.”
(Source: www3.uni-bonn.de)
Filed under brain brain areas risk perception risk takers economic game neuroscience psychology science
BrainHealth Team Studies Overeating as a Type of Addiction
A similar, insidious craving plagues all addicts, no matter the substance of choice. A new study published in NeuroImage from Center for BrainHealth scientists Dr. Francesca Filbey, assistant professor in the School of Behavioral and Brain Sciences, and doctoral student Samuel DeWitt has found that for binge-eaters, as with all addiction sufferers, the compulsion to overeat is rooted in the brain’s reward center.
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Filed under obesity overeating binge-eating reward system addiction neuroscience psychology science
Study pinpoints brain area’s role in learning
An area of the brain called the orbitofrontal cortex is responsible for decisions made on the spur of the moment, but not those made based on prior experience or habit, according to a new basic science study from substance abuse researchers at the University of Maryland School of Medicine and the National Institute on Drug Abuse (NIDA). Scientists had previously believed that the area of the brain was responsible for both types of behavior and decision-making. The distinction is critical to understanding the neurobiology of decision-making, particularly with regard to substance abuse. The study was published online in the journal Science.
Scientists have assumed that the orbitofrontal cortex plays a role in “value-based” decision-making, when a person compares options and weights consequences and rewards to choose best alternative. The Science study shows that this area of the brain is involved in decision-making only when the value must be inferred or computed rapidly or hastily. If the value has been “cached” or pre-computed, like a habit, then the orbitofrontal cortex is not necessary.
The same is true for learning — if a person infers an outcome but it does not happen, the resulting error can drive learning. The study shows that the orbitofrontal cortex is necessary for the inferred value that is used for this type of learning.
"Our research showed that damage to the orbitofrontal cortex may decrease a person’s ability to use prior experience to make good decisions on the fly," says lead author Joshua Jones, Ph.D., a postdoctoral researcher at the University of Maryland School of Medicine and a research scientist at NIDA, part of the National Institutes of Health. "The person isn’t able to consider the whole continuum of the decision — the mind’s map of how choices play out further down the road. Instead, the person is going to regress to habitual behavior, gravitating toward the choice that provides the most value in its immediate reward."
The study enhances scientists’ understanding of how the brain works in healthy and unhealthy individuals, according to the researchers.
"This discovery has general implications in understanding how the brain processes information to help us make good decisions and to learn from our mistakes," says senior author Geoffrey Schoenbaum, M.D., Ph.D., adjunct professor at the University of Maryland School of Medicine and senior investigator and chief of the Cellular Neurobiology Research Branch at NIDA. "Understanding more about the orbitofrontal cortex also is important for understanding disorders such as addiction that seem to involve maladaptive decision-making and learning. Cocaine in particular seems to have long-lasting effects on the orbitofrontal cortex. One aspect of this work, which we are pursuing, is that perhaps some of the problems that characterize addiction are the result of drug-induced changes in this area of the brain."
(Image: iStock)
Filed under brain orbitofrontal cortex substance abuse learning decision-making neuroscience psychology science
Combination of two pharmaceuticals proves effective in the treatment of multiple sclerosis
A new substance class for the treatment of multiple sclerosis and other neurodegenerative diseases now promises increased efficacy paired with fewer side effects. To achieve this, a team of scientists under the leadership of Prof. Gunter Fischer (Max Planck Research Unit for Enzymology of Protein Folding, Halle/Saale, Germany) and Dr. Frank Striggow (German Center for Neurodegenerative Diseases (DZNE)) have combined two already approved pharmaceutical substances with each other using a chemical linker structure. The objectives of this combination are to ensure maximum brain cell protection on the one hand and the suppression of unwanted side effects on the other. The new class of substances has now been registered with the European Patent Office as the DZNE’s first patent in the form of a joint patent application with the Max Planck Research Unit. “The patent approval process can take several years. During this phase we are planning to conclude the pre-clinical development. It is our aim to start with clinical research and development at the earliest possible time. Overall, we have identified substantial therapeutic potential as far as chronic and age-related neurodegenerative diseases are concerned,” comments Dr. Frank Striggow.
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Filed under MS pharmaceutical substances treatment immunosuppressants nerve cells neuroscience science
To Get the Best Look at a Person’s Face, Look Just Below the Eyes
They say that the eyes are the windows to the soul. However, to get a real idea of what a person is up to, according to UC Santa Barbara researchers Miguel Eckstein and Matt Peterson, the best place to check is right below the eyes. Their findings are published in the Proceedings of the National Academy of Science.
"It’s pretty fast, it’s effortless –– we’re not really aware of what we’re doing," said Miguel Eckstein, professor of psychology in the Department of Psychological & Brain Sciences. Using an eye tracker and more than 100 photos of faces and participants, Eckstein and graduate research assistant Peterson followed the gaze of the experiment’s participants to determine where they look in the first crucial moment of identifying a person’s identity, gender, and emotional state.
"For the majority of people, the first place we look at is somewhere in the middle, just below the eyes," Eckstein said. One possible reason could be that we are trained from youth to look there, because it’s polite in some cultures. Or, because it allows us to figure out where the person’s attention is focused.
However, Peterson and Eckstein hypothesize that, despite the ever-so-brief –– 250 millisecond –– glance, the relatively featureless point of focus, and the fact that we’re usually unaware that we’re doing it, the brain is actually using sophisticated computations to plan an eye movement that ensures the highest accuracy in tasks that are evolutionarily important in determining flight, fight, or love at first sight.
Filed under eye movements face perception face processing neuroscience psychology science
Scientists image brain structures that deteriorate in Parkinson’s
A new imaging technique developed at MIT offers the first glimpse of the degeneration of two brain structures affected by Parkinson’s disease.
The technique, which combines several types of magnetic resonance imaging (MRI), could allow doctors to better monitor patients’ progression and track the effectiveness of potential new treatments, says Suzanne Corkin, MIT professor emerita of neuroscience and leader of the research team. The first author of the paper is David Ziegler, who received his PhD in brain and cognitive sciences from MIT in 2011.
The study, appearing in the Nov. 26 online edition of the Archives of Neurology, is also the first to provide clinical evidence for the theory that Parkinson’s neurodegeneration begins deep in the brain and advances upward.
“This progression has never been shown in living people, and that’s what was special about this study. With our new imaging methods, we can see these structures more clearly than anyone had seen them before,” Corkin says.
Filed under brain neuroimaging parkinson's disease neurodegeneration neuroscience psychology science
