Posts Tagged ‘science’

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 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-/

Synthetic nanoparticles used to fight cancer could also heal sickly plants.

The particles, called liposomes, are nanosized, spherical pouches that can deliver drugs to specific parts of the body (SN: 12/16/06, p. 398). Now, researchers have filled these tiny care packages with fertilizing nutrients. The new liposomes, described online May 17 in Scientific Reports, soak into plant leaves more easily than naked nutrients. That allows the nanoparticles to give malnourished crops a more potent pick-me-up than the free-floating molecules in ordinary nutrient spray.

Each liposome is a hollow sphere about 100 nanometers across, and is made of fatty molecules extracted from soybean plants. Once a plant leaf absorbs these nanoparticles, the liposomes spread to cells in the plant’s other leaves and its roots, where the fatty envelopes break down and release their molecular cargo.

Researchers first exposed tomato plants to either liposomes packed with a rare earth metal called europium, or free-floating europium molecules. Europium doesn’t naturally exist in plants or soil, so it’s easy to trace how much of this element plants soaked up after treatment. Three days after exposure, plants treated with liposomes had absorbed up to 33 percent of the nanoparticles. Plants exposed to free-floating europium took in less than 0.1 percent of the molecules

The researchers then spritzed iron- and magnesium-deficient tomato plants with either a standard spray containing iron and magnesium, or a solution containing liposomes packed with those nutrients. Two weeks later, the leaves on plants treated with free-floating nutrients were still tinged yellow and curled. Plants that received liposome treatment sported healthy, green leaves.

Avi Schroeder, a chemical engineer at the Israel Institute of Technology in Haifa, and colleagues don’t know exactly why liposomes are more palatable to plants than plain nutrients. But sprays that contain nutrient-loaded liposomes could help farmers rejuvenate frail plants more efficiently than existing mixtures, Schroeder says.

Liposome-based spray would need to be tested on a variety of vegetation before it could enter widespread use, says Ramesh Raliya, a nanobiotechnology researcher at Washington University in St. Louis not involved in the work. That’s because the pores on leaves where liposomes are assumed to enter plants can range from 50 to 150 nanometers across. If a plant’s pores are smaller than 100 nanometers, the liposomes can’t squeeze inside.

Mariya Khodakovskaya, a biologist at the University of Arkansas at Little Rock, is wary of the potential cost of this new technique. Fashioning liposomes is expensive. That’s not a problem for making liposome-based medication, which requires only a small amount of nanoparticles. But for any new agricultural practice to take root, she says, “it has to be massive, and it has to be cheap.”

A. Karny et al. Therapeutic nanoparticles penetrate leaves and deliver nutrients to agricultural crops. Scientific Reports. Published online May 17, 2018. doi: 10.1038/s41598-018-25197-y.

https://www.sciencenews.org/article/nanoparticles-could-help-rescue-malnourished-crops


A NASA artist visualized what Earth would look like if it entered the “snowball state” predicted by new research from the University of Washington

By Chelsea Gohd

Earth-like planets with severe tilts and orbits could enter abrupt “snowball states,” in which entire oceans freeze and surface life cannot survive, according to new research.

Researchers at the University of Washington (UW) have found a new reason why, just because a planet is located in a “habitable zone” — meaning it’s close enough to its host star to sustain liquid water — it isn’t necessarily habitable. The team found that the axial tilt and orbital dynamics of planets in the habitable zone around “G dwarf” stars like our own sun can lead to “snowball states,” which are essentially extreme ice ages.

This new research looked at how a planet’s obliquity, or the angle at which a planet’s rotation axis tilts, and its orbital eccentricity, a parameter that determines the amount that an orbit deviates from a perfect circle, could affect that planet’s potential to be habitable.

Previous research suggested that planets in a habitable zone with a sun-like star that had a severe axial tilt or tilting orbit would be warmer, according to the statement. The team’s research found that the opposite holds true, which was quite a shock, they said.”We found that planets in the habitable zone could abruptly enter ‘snowball’ states if the eccentricity or the semi-major axis variations — changes in the distance between a planet and star over an orbit — were large or if the planet’s obliquity increased beyond 35 degrees,” Russell Deitrick, lead author of the new work and a postdoctoral researcher at the University of Bern who completed this research at UW, said in a statement.

Luckily, Earth’s axial tilt varies ever so slightly, leaving Earth “a relatively calm planet, climate-wise,” co-author Rory Barnes, an astronomer at UW, said in the statement. But, as it pertains to exoplanets, Deitrick “has essentially shown that ice ages on exoplanets can be much more severe than on Earth, that orbital dynamics can be a major driver of habitability and that the habitable zone is insufficient to characterize a planet’s habitability,” Barnes said.

A planet’s position in the habitable zone is typically a major factor in considering whether it may be habitable. However, this new research shows that even if a planet seems Earth-like and is orbiting at the right distance from its star, if “its orbit and obliquity oscillate like crazy, another planet might be better for follow-up with telescopes of the future,” Deitrick said.

With this research in mind, orbital dynamics should be considered an important part of determining a planet’s habitability, Deitrick added.

The work will be published in The Astronomical Journal, according to the statement.

https://www.space.com/40606-exoplanets-sudden-ice-age-snowball-states.html

Brown University researchers studying the biology of aging have demonstrated a new strategy for stimulating autophagy, the process by which cells rebuild themselves by recycling their own worn-out parts.

In a study published in the journal Cell Reports, the researchers show that the approach increased the lifespans of worms and flies, and experiments in human cells hint that the strategy could be useful in future treatments for Alzheimer’s disease, ALS and other age-related neurodegenerative conditions.

“Autophagy dysfunction is present across a range of age-related diseases including neurodegeneration,” said Louis Lapierre, an assistant professor of molecular biology, cell biology and biochemistry at Brown who led the work. “We and others think that by learning how to influence this process pharmacologically, we might be able to affect the progression of these diseases. What we’ve shown here is a new and conserved entry point for stimulating autophagy.”

Autophagy has become a hot topic in recent years, earning its discoverer the Nobel Prize in Physiology and Medicine in 2016. The process involves the rounding up of misfolded proteins and obsolete organelles within a cell into vesicles called autophagosomes. The autophagosomes then fuse with a lysosome, an enzyme-containing organelle that breaks down those cellular macromolecules and converts it into components the cell can re-use.

Lapierre and his colleagues wanted to see if they could increase autophagy by manipulating a transcription factor (a protein that turns gene expression on and off) that regulates autophagic activity. In order for the transcription factor to switch autophagic activity on, it needs to be localized in the nucleus of a cell. So Lapierre and his team screened for genes that enhance the level of the autophagy transcription factor, known as TFEB, within nuclei.

Using the nematode C. elegans, the screen found that reducing the expression of a protein called XPO1, which transports proteins out of the nucleus, leads to nuclear accumulation of the nematode version of TFEB. That accumulation was associated with an increase in markers of autophagy, including increased autophagosome, autolysosomes as well as increased lysosome biogenesis. There was also a marked increase in lifespan among the treated nematodes of between about 15 and 45 percent.

“What we showed was that by blocking the escape of this transcription factor from the nucleus, we could not only influence autophagy but we could get an increase in lifespan as well,” Lapierre said.

The next step was to see if there were drugs that could mimic the effect of the gene inhibition used in the screening experiment. The researchers found that selective inhibitors of nuclear export (SINE), originally developed to inhibit XPO1 to treat cancers, had a similar effect — increasing markers of autophagy and significantly increasing lifespan in nematodes.

The researchers then tested SINE on a genetically modified fruit fly that serves as a model organism for the neurodegenerative disease ALS. Those experiments showed a small but significant increase in the lifespans of the treated flies. “Our data suggests that these compounds can alleviate some of the neurodegeneration in these flies,” Lapierre said.

As a final step, the researchers set out to see if XPO1 inhibition had similar effects on autophagy in human cells as it had in the nematodes. After treating a culture of human HeLa cells with SINE, the researchers found that, indeed, TFEB concentrations in nuclei increased, as did markers of autophagic activity and lysosomal biogenesis.

“Our study tells us that the regulation of the intracellular partitioning of TFEB is conserved from nematodes to humans and that SINE could stimulate autophagy in humans,” Lapierre said. “SINE have been recently shown in clinical trials for cancer to be tolerated, so the potential for using SINE to treat other age-related diseases is there.”

Future research, Lapierre said, will focus on testing these drugs in more clinically relevant models of neurodegenerative diseases. But this initial research is a proof of concept for this strategy as a means to increase autophagy and potentially treat age-related diseases.

Lapierre is a faculty member in the newly approved Center on the Biology of Aging within the Brown Institute for Translational Science. This center, led by Professor of Biology John Sedivy, studies the biological mechanisms of aging. The center’s mission is to expand biomedical research and education programs in the emerging discipline of biogerontology, and to bring forth scientific discoveries related to aging and associated disorders.