Posts Tagged ‘brain’

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.”


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 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.

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.

By Jeanna Bryner

An auditory illusion that’s making the rounds online seems to have divided people into passionate camps depending on whether they hear the word “Yanny” or “Laurel” when listening to a recording.

If you hear one, you don’t hear the other, and you’ll be convinced the audio clip could only be saying … “Laurel” (in my case). Are you #teamyanny or #teamlaurel?

There’s some science to suggest that depending on how you look at the explanation, either both teams are correct or neither are. That’s because no “true” word has been recorded, Andrew Oxenham, a professor in the Departments of Psychology and Otolaryngology at the University of Minnesota, told Live Science.

The illusion first popped up on Reddit a few days ago. It is being likened to the famous dress debate of 2015, in which some people swore the garment was black and blue and others said it was white and gold. According to a study of that illusion, people saw the different colors because of assumptions the brain made about the illumination of the dress under different lighting conditions.

Filling in missing information
This latest “illusion,” although based on auditory perception and not vision, also likely boils down to the brain’s wackiness. One idea is that, if there is any ambiguity about a sound or word, the brain will lock onto one word or sound and deem that the correct interpretation. When there is a “perceptually ambiguous stimulus,” the University of Sydney’s David Alais told The Guardian, “the brain locks on to a single perceptual interpretation. Here, the Yanny/Laurel sound is meant to be ambiguous because each sound has a similar timing and energy content — so, in principle, it’s confusable.”

Alais, who studies audiovisual perception, added, “All of this goes to highlight just how much the brain is an active interpreter of sensory input, and thus that the external world is less objective than we like to believe.”

Researchers are saying it’s the auditory version of the so-called Rubin’s vase, an image that is visually ambiguous and can be interpreted in one of two ways: as the profiles of two people, or a vase, according to various news reports on the illusion.

Because your brain plays tricks on you here, your expectations about what you’ll hear, or even your past experiences, could shape whether you feel strongly about Team Yanny or Team Laurel, The Guardian reported.

In addition to sending vital auditory clues to your brain, your ears play a role in this maddening Yanny/Laurel interpretation. Each sound is made up of several frequencies, and those that create “Yanny” are higher than those for “Laurel,” said Lars Riecke, a cognitive neuroscientist at Maastricht University in the Netherlands, as reported by The Verge. The speakers you’re using may change the frequency, leading to the different interpretations, he added.

But your ear shape and your age could also play roles. Turns out, as people age, they start to lose the ability to hear the higher sounds, so they may be more likely to hear “Laurel,” which was the case for Alais, who is 52.

Sound frequencies
“Basically, there is no ‘true’ word and the stimulus has ‘clues’ based on the formant frequencies that point to either one or the other word,” Oxenham said. A formant refers to the frequencies that carry the most energy when a sound is made, and they depend on the different parts of a person’s vocal tract.

The shape of the tract and the resulting frequencies that come out when a person speaks are due to the placement of the tongue, according to psycholinguist Suzy Styles of the Nanyang Technological University, who tweeted about the Yanny/Laurel puzzle.

It seems like a speech synthesizer must have created the clip, according to Oxram and Styles. In normal speech, Styles tweeted, there are three formants that a person produces, but in this clip, there are more than three.

“So unless this speaker had two completely separate tongues, this ambiguous speech has been carefully crafted to fool the ears. Shall we call it an Ear-llusion?,” Styles tweeted.

Reportedly, if you mess with the sound on your speakers to remove the high frequencies, you’ll hear “Laurel” and vice versa when you remove the lower frequencies.

Why Laurel or Yanny?
As for what makes a person sway one way or the other after listening to this audio clip, that’s anyone’s guess for now.

“I’m not sure that anyone knows why some people hear it one way and other people hear it another way, but that’s often the way with these visual and auditory illusions — our brains ‘fill in’ missing information, and how that happens seems to vary a lot from one person to the next,” Oxenham said.

Bharath Chandrasekaran, an associate professor in the Department of Communication Sciences and Disorders at the University of Texas at Austin, said he doesn’t know either, but he’s planning to find out. He told The Verge that he is going to look for volunteers in both camps and then run tests in which he looks at their brain waves while they listen to the audio clip.

The dentate gyrus of a mouse that received deep brain stimulation, with cell nuclei in blue and expression of the gene c-Fos in red.

By Shawna Williams

Even as patients with Parkinson’s disease, obsessive-compulsive disorder, and other conditions turn to deep brain stimulation (DBS) to keep their symptoms in check, it’s been unclear to scientists why the therapy works. Now, researchers in Texas report that in mice, the treatment dials the activity of hundreds of genes up or down in brain cells. Their results, published in eLife March 23, hint that DBS’s use could be expanded to include improving learning and memory in people with intellectual disabilities.

“The paper is very well done. . . . It’s really a rigorous study,” says Zhaolan “Joe” Zhou, a neuroscientist at the University of Pennsylvania’s Perelman School of Medicine who reviewed the paper for eLife. Now that the genes and pathways DBS affects are known, researchers can home in on ways to improve the treatment, or perhaps combine the therapy with pharmacological approaches to boost its effect, he says.

In DBS, two electrodes are surgically implanted in a patient’s brain (the area depends on the disorder being treated), and connected to generators that are placed in the chest. Gentle pulses of electricity are then passed continuously through the electrodes. The treatment reduces motor symptoms in many people with Parkinson’s, and allows some patients to reduce their use of medications, but it does not eliminate symptoms or slow the disease’s progression.

In addition to its use in movement disorders, DBS is being explored as a potential therapy for a range of other brain-related disorders. For instance, as a way to boost learning and memory in people with Alzheimer’s disease, researchers are looking into stimulating the fimbria-fornix, a brain region thought to regulate the activity of the memory-storing hippocampus.

Such studies made Huda Zoghbi, a neurogeneticist at Baylor College of Medicine, wonder what effect DBS might have on learning- and memory-related disorders that strike earlier in life. “We rationalized that maybe in Alzheimer’s, many of the neurons are already gone, but perhaps in a healthier brain, like that of a Rett syndrome model, we can test the idea if stimulation of the fornix can improve learning and memory,” she explains. Rett syndrome, a genetic disease that almost exclusively strikes girls, includes intellectual disability, autism-like deficits in social interactions, and a loss of motor function. Several years ago, Zoghbi and colleagues tried zapping the fimbria-fornix, a C-shape bundle of nerves adjacent to the hippocampus in the brain, in mouse models of Rett syndrome. Published in 2015, their results showed that after two weeks of daily, one-hour DBS sessions, the mice with an intellectual disability performed like their peers without the disorder on a range of hippocampus-dependent tasks.

“We were struck that everything became indistinguishable after deep brain stimulation from a baseline normal,” Zoghbi says. This prompted her team to ask, “How does it work at a molecular level?” The answer, she thought, could determine whether DBS of the fimbria-fornix has the potential to serve as a multipurpose tool, treating not just Rett syndrome but other childhood-onset intellectual disabilities with a variety of causes. “It’s going to be really tough, perhaps, to solve these diseases one gene at a time, so that learning can be corrected,” she says. “You could eventually consider an intervention that can be broadly applicable, irrespective of the molecular cause of the defect.”

For the latest study, the research team analyzed baseline differences in gene activity between mice with and without the Rett syndrome–like condition in a part of the hippocampus called the dentate gyrus. They also treated the mice with the intellectual disability once with 45 minutes of DBS. Of the many genes with marked differences in initial activity between the two groups of mice, one-quarter (39 genes) became normal in the Rett mice after treatment, they report.

Zoghbi’s group also tested the effects of DBS in normal mice; in addition to changing the activity levels of thousands of genes, the researchers found, the treatment prompted alternative splicing of the RNA copies of other genes, which would result in differences in the resulting proteins. Many of the genes affected by the alternative splicing are known to be involved in the growth of new neurons or in maintaining the synapses through which brain cells communicate. In the 2015 study, the group had found that DBS enhances some hippocampus-related abilities in wildtype mice, such as spatial learning.

For hints as to whether DBS might have the potential to treat intellectual disabilities other than Rett syndrome, the researchers compared their list of genes whose activity levels changed after DBS in normal mice with existing data on genes known to have abnormal expression levels in mouse models of several such disorders. As with Rett syndrome, DBS in wildtype mice altered the activity levels of about one-quarter of the genes involved in each of the disorders.

The fact that a short period of stimulation had such profound effects on gene expression is interesting, says Svjetlana Miocinovic, a movement-disorders neurologist at Emory University who was not involved in the study. Most research on the mechanism of DBS has focused on changes it induces in the electrical or physical properties of the brain, she tells The Scientist. “I think this kind of study, where they actually look at the molecular environment in these neurons that are exposed to stimulation . . . is really the way to figure out what exactly is going on and how is that neural plasticity accomplished.”

Now that they have a way to measure such molecular effects, Zoghbi and her collaborators plan to optimize DBS for models of intellectual disabilities—figuring out how long the current needs to be on, for example, and how often. Another question they’d like to address is whether stimulating other brain areas in addition to the fimbria-fornix could add to the benefits seen in the mice.

Zoghbi emphasizes that even if DBS turns out to be safe and effective for children with Rett syndrome, it won’t be a silver bullet, because patients will have missed out on some important developmental milestones. “To really get the full benefit,” she says, “we’re going to have to combine any intervention with intensive physical and behavioral therapy.”

A. Pohodish et al., “Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity,” eLife, doi:10.7554/eLife.34031, 2018.

The Dr. Peter Stys lab within the Hotchkiss Brain Institute at the Cumming School of Medicine, University of Calgary, is equipped with highly specialized microscopes used for researching multiple sclerosis, Alzheimer’s and other neurodegenerative disease. In this customized lab, the researchers can’t wear white lab coats, they have to wear dark clothing. Photons could reflect off light clothing and interfere with the experiments. From left: Megan Morgan, research assistant, and Craig Brideau, engineering scientist. Photo by Pauline Zulueta, Cumming School of Medicine

By Kelly Johnston, Cumming School of Medicine

Ridiculous. That’s how Andrew Caprariello says his colleagues described his theory about multiple sclerosis (MS) back when he was doing his PhD in Ohio.

Caprariello’s passion to explore controversial new theories about MS propelled him to seek out a postdoctoral fellowship with a like-minded thinker, whom he found in University of Calgary’s Dr. Peter Stys, a member of the Hotchkiss Brain Institute at the Cumming School of Medicine (CSM).

The collaboration paid off. Caprariello, Stys and their colleagues have scientific proof published in the Proceedings of the National Academy of Sciences (PNAS) that their somewhat radical theory has merit. “I’ve always wondered ‘what if’ MS starts in the brain and the immune attacks are a consequence of the brain damage,” says Caprariello, PhD, and lead author on the study.

Currently, MS is considered to be a progressive autoimmune disease. Brain inflammation happens when the body’s immune system attacks a protective material around nerve fibers in the brain called myelin. Conventional thinking is that rogue immune cells initially enter the brain and cause myelin damage that starts MS.

“In the field, the controversy about what starts MS has been brewing for more than a decade. In medical school, I was taught years ago that the immune attack initiates the disease. End of story,” says Stys, a neurologist and professor in the Department of Clinical Neurosciences at the CSM. “However, our findings show there may be something happening deeper and earlier that damages the myelin and then later triggers the immune attacks.”

To test the theory, the research team designed a mouse model of MS that begins with a mild myelin injury. In this way, researchers could mirror what they believe to be the earliest stages of the disease.

“Our experiments show, at least in this animal model, that a subtle early biochemical injury to myelin secondarily triggers an immune response that leads to additional damage due to inflammation. It looks very much like an MS plaque on MRI and tissue examination,” says Stys. “This does not prove that human MS advances in the same way, but provides compelling evidence that MS could also begin this way.”

With that result, the researchers started to investigate treatments to stop the degeneration of the myelin to see if that could reduce, or stop, the secondary autoimmune response.

“We collaborated with researchers at the University of Toronto and found that by targeting a treatment that would protect the myelin to stop the deterioration, the immune attack stopped and the inflammation in the brain never occurred,” says Stys. “This research opens a whole new line of thinking about this disease. Most of the science and treatment for MS has been targeted at the immune system, and while anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stages of the disease when most disability happens.”

It can be very hard to find funding to investigate an unconventional theory. The research team was funded by the Brain and Mental Health Strategic Research Fund, established by the Office of the Vice-President (Research) at UCalgary to support innovative, interdisciplinary studies within the Brain and Mental Health research strategy.

“We chose high-risk, novel projects for these funds to support discoveries by teams who did not have the chance to work together through conventional funding sources,” said Ed McCauley, PhD, vice-president (research). “The MS study shows the potential of brain and mental health scholars to expand capacity by tapping into new approaches for conducting research. Their work also exemplifies the type of interdisciplinary research that is propelling the University of Calgary as an international leader in brain and mental health research.”

In a new study researchers from the Institute for Experimental Pediatric Endocrinology of the Charité – Universitätsmedizin Berlin have successfully treat patients whose obesity is caused by a genetic defect. Aside from its beneficial effects on the patients, the researchers also provided insights into the fundamental signaling pathways regulating satiety of the new drug. The results of this research have been published in Nature Medicine*.

A mutation in the gene encoding the leptin receptor (LEPR) can cause extreme hunger starting with the first months of life. As a result, affected individuals develop extreme obesity during childhood. Increased exercise and reduced caloric intake are usually insufficient to stabilize body-weight. In many cases, obesity surgery fails to deliver any benefits, meaning that a drug-based treatment approach becomes increasingly important.

Two years ago, Dr. Peter Kühnen and the working group successfully demonstrated that treatment with a peptide, which activates the melanocortin 4 receptor (MC4R) could play a central role in the body’s energy metabolism and body weight regulation. Leptin, which is also known as the satiety (or starvation) hormone, normally binds to the LEPR, triggering a series of steps that leads to the production of melanocyte-stimulating hormone (MSH). The act of MSH by binding to its receptor, the melanocortin 4 receptor (MC4R) which transduce the satiety signal to the body. However, if the LEPR is defective, the signaling cascade is interrupted. The patient’s hunger remains unabated, placing them at greater risk of becoming obese. As part of this current study, researchers used a peptide that binds to the MC4R in the brain, and this activation trigger the normal satiety signal. Working in cooperation with the Clinical Research Unit at the Berlin Institute of Health (BIH), the researchers were able to record significant weight loss in patients with genetic defects affecting the LEPR.

“We also wanted to determine why the used peptide was so effective and why, in contrast to other preparations with a similar mode of action, it did not produce any severe side effects,” explains Dr. Kühnen. “We were able to demonstrate that this treatment leads to the activation of a specific and important signaling pathway, whose significance had previously been underestimated.” Dr. Kühnen’s team is planning to conduct further research to determine whether other patients might benefit from this drug: “It is possible that other groups of patients with dysfunctions affecting the same signaling pathway might be suitable candidates for this treatment.”

*Clément K, et al., MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency, Nature Medicine (2018), doi:10.1038/s41591-018-0015-9.