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Scientists have just discovered that a small region of a cellular protein that helps long-term memories form also drives the neurodegeneration seen in motor neuron disease (MND). This small part of the Ataxin-2 protein thus works for good and for bad. When a version of the protein lacking this region was substituted for the normal form in fruit flies (model organisms), the animals could not form long-term memories – but, surprisingly, the same flies showed a remarkable resistance to neurodegeneration.

The popular “ice bucket challenge” highlighted the social significance of MND, as well as the need to better understand and treat neurodegenerative conditions. This new research identifies a very specific basic mechanism that facilitates progression of neuronal loss in an animal model of MND, and, by shedding light on a potential way to protect against cell death in MND, it should inform strategies for the development of therapeutics to treat or manage these devastating conditions, which are currently incurable.

The Science Foundation Ireland-funded research, involving scientists from the Trinity College Institute of Neuroscience, NCBS Bangalore and HMMI, University of Colorado, Boulder, has just been published in the leading international journal Neuron.

Professor of Neurogenetics at Trinity College Dublin, Mani Ramaswami, said: “This work, by collaborating young researchers based in Irish, Indian and American laboratories, provides a great example of the ability of fundamental research in model organisms to produce biologically and clinically interesting information.”

A common feature of neurodegenerative diseases is the presence of specific protein aggregates in nerve cells, which accumulate and clump together — usually as protein fibres called amyloid filaments. Such aggregates are believed to trigger processes that cause the neuronal death associated with these debilitating diseases. For example, amyloid-beta (Aβ) aggregates are associated with Alzheimer’s disease, while TDP-43, FUS and Ataxin-2 proteins are commonly found in MND patients.

The scientists behind the current study set out to test this “amyloid hypothesis” to see whether it may explain how MND develops. The scientists genetically engineered fruit flies with mutations designed to reduce Ataxin-2 protein assembly into aggregates without affecting other functions of the protein.

Arnas Petrauskas, Trinity, said: “The flies with this altered, non-aggregating version of the protein showed a striking resistance to neurodegeneration. This suggests the normal Ataxin-2 protein and its ability to form aggregates is required for the progression of at least some forms of MND, which means these results provide support for the amyloid hypothesis.”

“What really surprised us though was that this same protein region seems to be required for the flies to develop long-term memory, as those with the altered version of Ataxin-2 showed normal short-term but defective long-term memories.”

Fruit flies normally respond strongly to new odorants, but weakly to familiar odorants through a process called habituation. This memory of the familiar can be of the short-term kind – to an odorant encountered for half-an-hour, or of the long-term kind, to odorants encountered for days (think of it as remembering a phone number of a new acquaintance versus remembering your own phone number). Flies lacking this small domain of Ataxin-2 showed greatly reduced long-term memory.

So how is long-term memory formation and disease progression connected? It turns out that proteins like the TDP-43, FUS and Ataxin-2 found in MND are also involved in the natural control and management of protein expression in the cell. The very same region of Ataxin-2 is needed to form RNP granules that store RNAs (essentially blueprints, or recipes for specific proteins) in a silent form until they are unpackaged by a signal and used to produce molecules when they are required. This local control of RNAs is required for long-term changes at neuronal synapses that underlie long-term memory.

The new discovery shows that Ataxin-2 concentrates several RNA-binding proteins used in the process of memory storing, but in doing so, it creates a biological environment that can help these proteins aggregate into disease-causing amyloids. A “trade-off” therefore exists in nature where the Ataxin-2 gene increases the danger of neurodegeneration, but helps our cells control RNA and form long-term memories.

In a commentary on the research published in the same issue of the journal Neuron, Aaron Gitler, Professor of Genetics in the Stanford Neuroscience Institute, an independent expert in MND research said: “This data suggest that manipulating RNP granule formation by genetically manipulating ataxin-2’s IDRs, or by other means could be therapeutic in ALS. Beyond ataxin-2, the race is now on to discover additional proteins that help build RNP granules.”

https://www.tcd.ie/news_events/articles/link-between-long-term-memory-and-neurodegenerative-disease/8941

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The purpose and evolutionary origins of sleep are among the biggest mysteries in neuroscience. Every complex animal, from the humblest fruit fly to the largest blue whale, sleeps — yet scientists can’t explain why any organism would leave itself vulnerable to predators, and unable to eat or mate, for a large portion of the day. Now, researchers have demonstrated for the first time that even an organism without a brain — a kind of jellyfish — shows sleep-like behaviour, suggesting that the origins of sleep are more primitive than thought.

Researchers observed that the rate at which Cassiopea jellyfish pulsed their bell decreased by one-third at night, and the animals were much slower to respond to external stimuli such as food or movement during that time. When deprived of their night-time rest, the jellies were less active the next day.

“Everyone we talk to has an opinion about whether or not jellyfish sleep. It really forces them to grapple with the question of what sleep is,” says Ravi Nath, the paper’s first author and a molecular geneticist at the California Institute of Technology (Caltech) in Pasadena. The study was published in Current Biology.

“This work provides compelling evidence for how early in evolution a sleep-like state evolved,” says Dion Dickman, a neuroscientist at the University of Southern California in Los Angeles.

Mindless sleep
Nath is studying sleep in the worm Caenorhabditis elegans, but whenever he presented his work at research conferences, other scientists scoffed at the idea that such a simple animal could sleep. The question got Nath thinking: how minimal can an animal’s nervous system get before the creature lacks the ability to sleep? Nath’s obsession soon infected his friends and fellow Caltech PhD students Michael Abrams and Claire Bedbrook. Abrams works on jellyfish, and he suggested that one of these creatures would be a suitable model organism, because jellies have neurons but no central nervous system. Instead, their neurons connect in a decentralized neural net.

Cassiopea jellyfish, in particular, caught the trio’s attention. Nicknamed the upside-down jellyfish because of its habit of sitting on the sea floor on its bell, with its tentacles waving upwards, Cassiopea rarely moves on its own. This made it easier for the researchers to design an automated system that used video to track the activity of the pulsing bell. To provide evidence of sleep-like behaviour in Cassiopea (or any other organism), the researchers needed to show a rapidly reversible period of decreased activity, or quiescence, with decreased responsiveness to stimuli. The behaviour also had to be driven by a need to sleep that increased the longer the jellyfish was awake, so that a day of reduced sleep would be followed by increased rest.

Other researchers had already documented a nightly drop in activity in other species of jellyfish, but no jellyfish had been known to display the other aspects of sleep behaviour. In a 35-litre tank, Nath, Abrams and Bedbrook tracked the bell pulses of Cassiopea over six days and nights and found that the rate, which was an average of one pulse per second by day, dropped by almost one-third at night. They also documented night-time pulse-free periods of 10–15 seconds, which didn’t occur during the day.

Restless night
Without an established jellyfish alarm clock, the scientists used a snack of brine shrimp and oyster roe to try to rouse the snoozing Cassiopea. When they dropped food in the tank at night, Cassiopea responded to its treat by returning to a daytime pattern of activity. The team used the jellyfish’s preference for sitting on solid surfaces to test whether quiescent Cassiopea had a delayed response to external stimuli. They slowly lifted the jellyfish off the bottom of the tank using a screen, then pulled it out from under the animal, leaving the jelly floating in the water. It took longer for the creature to begin pulsing and to reorient itself when this happened at night than it did during the day. If the experiment was immediately repeated at night, the jellyfish responded as if it were daytime. Lastly, when the team forced Cassiopea to pull an all-nighter by keeping it awake with repeated pulses of water, they found a 17% drop in activity the following day.

“This work shows that sleep is much older than we thought. The simplicity of these organisms is a door opener to understand why sleep evolved and what it does,” says Thomas Bosch, an evolutionary biologist at Kiel University in Germany. “Sleep can be traced back to these little metazoans — how much further does it go?” he asks.

That’s what Nath, Abrams and Bedbrook want to find out. Amid the chaos of finishing their PhD theses, they have begun searching for ancient genes that might control sleep, in the hope that this might provide hints as to why sleep originally evolved.

https://www.nature.com/news/jellyfish-caught-snoozing-give-clues-to-origin-of-sleep-1.22654

Writing in the journal eLife, the team reveals that this disease is caused by a recessive mutation in CAMK2A – a gene that is well known for its role in regulating learning and memory in animals. The findings suggest that dysfunctional CAMK2 genes may contribute to other neurological disorders, such as epilepsy and autism, opening up potential new avenues for treating these conditions.

“A significant number of children are born with growth delays, neurological defects and intellectual disabilities every year across the world,” explains senior author Bruno Reversade, Research Director at the Institute of Medical Biology and Institute of Molecular and Cell Biology, A*STAR, Singapore, who supervised the study. “While specific genetic mutations have been identified for some patients, the cause remains unknown in many cases. Identifying novel mutations would not only advance our understanding of neurological diseases in general, but would also help clinicians diagnose children with similar symptoms and/or carry out genetic testing for expecting parents.”

The team’s research began when they identified a pair of siblings who demonstrated neurodevelopmental delay with frequent, unexplained seizures and convulsions. While the structure of their bodies developed normally, they did not gain the ability to walk or speak. “We believed that the children had novel mutations in CAMK2A, and we wanted to see if this were true,” says Reversade.

The fully functional CAMK2A protein consists of multiple subunits. Using a genomic technique called exome sequencing, the team discovered a single coding error affecting a key residue in the CAMK2A gene that prevents its subunits from assembling correctly.

Moving their studies into the roundworm Caenorhabditis elegans, the scientists saw that this mutation disrupts the ability of CAMK2A to ensure proper neuronal communication and normal motor function. This suggests that the mutation is indeed the cause of the neurodevelopmental defects seen in the siblings.

To the best of the team’s knowledge, this new disorder represents the first human disease caused by inherited mutations on both copies of the CAMK2A gene. In addition, another report* published recently identified single-copy mutations on both CAMK2A and CAMK2B that caused intellectual disabilities as soon as the mutations occurred. “We would like to bring these findings to the attention of those working in the area of paediatric genetics, such as clinicians and genetic counsellors, as there are likely more undiagnosed children with similar symptoms who have mutations in their CAMK2A gene,” explains co-first author Franklin Zhong, Research Scientist in Reversade’s lab at A*STAR.

“Neuroscientists working to understand childhood brain development, neuronal function and memory formation also need to consider this new disease, since CAMK2A is associated with these processes. In future, it would be interesting to test whether restoring CAMK2A activity can bring therapeutic benefit to patients with this condition, as well as those with related neurological disorders.”

The paper ‘A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability‘ can be freely accessed online at https://doi.org/10.7554/eLife.32451. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

*Küry, S., van Woerden, G.M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., et al. (2017). De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. The American Journal of Human Genetics 101, 768-788.

https://www.technologynetworks.com/neuroscience/news/new-inherited-neurodevelopmental-disease-discovered-303233?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=63149617&_hsenc=p2ANqtz-_AJri5fciUzcysqtDye56dm2VpMIbIwRqkV2di9BmqZhzk9xuPEv5CWgKF24BpT8_OB1uWAjitxNXhmduWHyW2XKGlhw&_hsmi=63149617

By Sean Quinton

This is a tale of a rabbit, a fox and an eagle — but it’s no bedtime story.

An incredible display of nature unfolded Saturday on San Juan Island as a young fox quickly learned a valuable lesson about the pecking order in the Northwest wilderness.

A fox kit pranced along the prairie of San Juan Island National Historical Park with a rabbit clenched in its jaws, apparently pleased with its catch. Then the predator pauses abruptly, looks up and sees a bald eagle coming its way. The predator becomes the prey.

The fox tumbles and spins, and the eagle swoops to take hold of the rabbit. Both the rabbit and the fox are lifted into the air. The eagle flaps its wings. The fox doesn’t give up right away, flailing its young legs.

But the bird is too much for the red fox, which lets go of the rabbit and falls twirling back to the ground. The bird of prey won the battle.

The eight-second spectacle was captured on video.

Zachary Hartje was shooting photos when he anticipated what was about to happen in the prairie. He switched his camera to video mode.

“I was totally shocked,” he said. “No one I had ever talked to had ever seen anything like that.”

Hartje recently graduated from Gonzaga University and goes to the San Juan Islands several times a year to film and photograph the foxes there.

“It was a baby fox, so it might’ve been its first kill,” he said. “The fox just ran away into the den after. It looked pretty scared.”

Another photographer, Kevin Ebi, was also there to watch the fox kits.

“When I heard the bald eagle calling, I knew exactly what was going to happen,” Ebi said, who posted his photos to his blog, LivingWilderness.com. “I knew it wanted that rabbit.”

“After I saw the eagle finally drop the fox … I thought, ‘This is one of the most incredible things I’ve ever seen.’ “

Ebi said he has photographed eagles for years. He even published a book called “Year of the Eagle,” which chronicles the life of the Pacific Northwest birds. Even for him, the event was unprecedented.

Ebi said eagles don’t like to expend more calories than they need to get food, so when they see some other animal that’s already done the work of hunting, they might try to swoop in to steal a meal. The behavior is called kleptoparasitism.

Saturday’s confrontation was on another level. “This is the most difficult attempt I’ve ever seen and it’s extremely uncommon,” Ebi said.

The fox appeared to escape without injury, but next time it might think twice before taking its prey across the prairie.

By Ruth Williams

The sun’s ultraviolet (UV) radiation is a major cause of skin cancer, but it offers some health benefits too, such as boosting production of essential vitamin D and improving mood. A recent report in Cell adds enhanced learning and memory to UV’s unexpected benefits.

Researchers have discovered that, in mice, exposure to UV light activates a molecular pathway that increases production of the brain chemical glutamate, heightening the animals’ ability to learn and remember.

“The subject is of strong interest, because it provides additional support for the recently proposed theory of ultraviolet light’s regulation of the brain and central neuroendocrine system,” dermatologist Andrzej Slominski of the University of Alabama who was not involved in the research writes in an email to The Scientist.

“It’s an interesting and timely paper investigating the skin-brain connection,” notes skin scientist Martin Steinhoff of University College Dublin’s Center for Biomedical Engineering who also did not participate in the research. “The authors make an interesting observation linking moderate UV exposure to . . . [production of] the molecule urocanic acid. They hypothesize that this molecule enters the brain, activates glutaminergic neurons through glutamate release, and that memory and learning are increased.”

While the work is “fascinating, very meticulous, and extremely detailed,” says dermatologist David Fisher of Massachusetts General Hospital and Harvard Medical School, “it does not imply that UV is actually good for you. . . . Across the board, for humanity, UV really is dangerous.”

Wei Xiong of the University of Science and Technology of China who led the research did not set out to investigate the effects of UV light on the brain or the skin-brain connection. He stumbled upon his initial finding “almost accidentally,” he explains in an email to The Scientist. Xiong and his colleagues were using a mass spectrometry technique they had recently developed for analyzing the molecular contents of single neurons, when their results revealed the unexpected presence of urocanic acid—a little-known molecule produced in the skin in response to UV light.

“It was a surprise because we checked through all the literature and found no reports of the existence of this small molecule in the central nervous system,” writes Xiong.

With little information to go on, Xiong and his colleagues decided to see whether UV light could also boost levels of urocanic acid in the brain. They exposed shaved mice to a low-dose of UVB—responsible for sunburn in humans—for 2 hours, then performed mass spectrometry on the animals’ individual brain cells. Sure enough, levels of urocanic acid increased in neurons of the animals exposed to the light, but not in those of control animals.

Urocanic acid can absorb UV rays and, as a result, may be able to protect skin against the sun’s harmful effects. But in the liver and other peripheral tissues, the acid is also known to be an intermediate molecule generated in the metabolic pathway that converts histidine to glutamate. Given glutamate’s role in the brain as an excitatory neurotransmitter, Xiong and his colleagues were interested to test whether the observed UV-dependent increase in urocanic acid in neurons might be coupled with increased glutamate production. It was.

Next, the team showed that UV light enhanced electrical transmission between glutaminergic neurons in brain slices taken from animals exposed to UV, but not in those from control animals. This UV-induced effect was prevented when the researchers inhibited activity of the enzyme urocanase, which converts urocanic acid to glutamate, indicating that the acid was indeed the mediator of the UV-induced boost in glutaminergic activity.

Lastly, the team showed that mice exposed to UV performed better in motor learning and recognition memory tasks than their unexposed counterparts. And, as before, treating the animals with a urocanase inhibitor prevented the UV-induced improvements in learning and memory. Administering urocanic acid directly to animals not exposed to ultraviolet light also spurred similar learning and memory improvements to those achieved with UV exposure.

Whether the results obtained in mice, which are nocturnal and rarely see the sun, will hold true in humans is yet to be determined. But, Fisher says, if the results do hold, the finding that urocanic acid alone can enhance learning and memory might suggest “a way to utilize this information to benefit people without exposing them to the damaging effects of UV.”

H. Zhu et al., “Moderate UV exposure enhances learning and memory by promoting a novel glutamate biosynthetic pathway in the brain,” Cell, doi: 10.1016/j.cell.2018.04.014, 2018.

https://www.the-scientist.com/?articles.view/articleNo/54603/title/Could-a-Dose-of-Sunshine-Make-You-Smarter-/

by MELISSA BREYER

If there’s a single way of eating that persists in laying claim as one of the healthiest, it’s the Mediterranean diet. Experts continue to sing the praises of eating plenty of olive oil, plant foods, fish and wine.

The latest research — following several years of headline-making studies — makes it hard to argue with them.

Following a Mediterranean diet can protect against the harmful effects of air pollution, according to a 2018 study conducted by New York University. The study analyzed about 550,000 people for 17 years and factored in their level of exposure to pollution. Those who followed the Mediterranean diet compared to those who didn’t had a lower risk of dying from cardiovascular disease and heart attacks.

“Air pollution is hypothesized to cause bad health effects through oxidative stress and inflammation, and the Mediterranean diet is really rich in foods that are anti-inflammatory and have antioxidants that might intervene through those avenues,” said study author Chris Lim on Time.com.

It’s worth noting that the diet doesn’t protect against ozone exposure. (Researchers believe that ozone exposure effects the cardiac system differently.)

Why the hits keep on coming

Researchers have been uncovering the benefits of this particular diet for years. In fact, the diet’s benefits for heart health were so clear in one 2013 study that researchers ended the study early, saying it was unethical to continue.

Research from 2014 added to the accolades. Scientists in Boston looked at the nutritional data from 4,676 women participating in the Harvard Nurses’ Health Study — the well-known ongoing prospective cohort analysis ­— and discovered that those whose food choices most closely followed a Mediterranean diet had longer telomeres. Telomeres are the protective buffers on the ends of chromosomes and can be used as a biomarker of aging; the longer they are, the better.

“We know that having shorter telomeres is associated with a lower life expectancy and a greater risk of cancer, heart disease and other diseases,” said study coauthor Immaculata De Vivo, an associate professor of medicine at Brigham and Women’s Hospital. “Certain lifestyle factors like obesity, sugary sodas, and smoking have been found to accelerate telomere shortening, and now our research suggests the Mediterranean diet can slow this shortening.”

The key is cell aging

The Mediterranean diet isn’t a specific diet plan per se, but rather eating in the traditional style of those living in Mediterranean countries. It’s characterized by consuming a lot of vegetables, fruits, nuts, legumes and unrefined grains. There is plenty of olive oil, but little saturated fat; a moderate intake of fish, but little dairy, meat and poultry. And while cookies and sugar are limited, a regular but moderate dose of wine is involved.

It’s thought that the antioxidants present in the favored foods protect against cell aging. While the researchers didn’t find that any specific food provided the silver bullet, they suggest that it was a combination of the components that predicted telomere length.

The researchers scored each woman’s diet according to how closely it adhered to Mediterranean components. What they found was that each one-point change in their grading system equated to an extra year and a half of life. A three-point change, the study notes, would correspond to an average 4.5 years of aging, which is comparable to the difference between smokers with non-smokers.

The researchers also concluded that women who may have veered slightly from the Mediterranean diet but who still ate a healthy diet — like eating chicken and low-fat dairy products in addition to the Mediterranean basics — also had longer telomeres than those who ate a standard American diet with red meat, saturated fats, sweets and empty calories. Those who followed the Mediterranean diet, however, had the longest telomeres on average.

https://www.mnn.com/food/healthy-eating/stories/mediterranean-diet-could-add-years-to-your-life


The urge to rebel against control over one’s decisions is associated with the connectivity between parietal and frontal brain regions (shown in color). The stronger the synchronous activation was in these regions, the more likely were the participants to show defiant behavior.

Control aversion — the urge to rebel against control over one’s decisions — can be explained by connectivity between two regions of the brain as well as behavioral measures of distrust and lack of understanding, according to a study of university students published in JNeurosci.

Individual differences in control aversion are well-documented and can interfere with important decisions, such as whether or not to vaccinate a child. To understand what drives these differences, Sarah Rudorf, Daria Knoch, and colleagues had participants play a game in which they divided money between themselves and another player, who could decide to restrict the participant’s choice by asking for a minimum amount. Participants were informed that they would be compensated based on a randomly selected trial.

Connectivity between the parietal lobule and dorsolateral prefrontal cortex predicted the average difference in the chosen allocation level between the free choice and controlled conditions. Control aversion was also predicted by participants’ reported feelings about the other player’s trust in them and understanding of the other player’s request for a minimum amount of money. By combining a social decision-making task with real consequences, this neuroimaging research provides new insight into the influence of choice restriction on personal decisions.

Journal Reference:

Sarah Rudorf, Katrin Schmelz, Thomas Baumgartner, Roland Wiest, Urs Fischbacher, Daria Knoch. Neural mechanisms underlying individual differences in control-averse behavior. The Journal of Neuroscience, 2018; 0047-18 DOI: 10.1523/JNEUROSCI.0047-18.2018

https://www.sciencedaily.com/releases/2018/05/180515081753.htm