Posts tagged C. Elegans
Articles and news from the latest research reports.
Are Male Brains Wired to Ignore Food for Sex?
Choosing between two good things can be tough. When animals must decide between feeding and mating, it can get even trickier. In a discovery that might ring true even for some humans, researchers have shown that male brains – at least in nematodes – will suppress the ability to locate food in order to instead focus on finding a mate.
(Image caption: C. elegans male (top) and hermaphrodite (bottom))
The results, which appear today in the journal Current Biology, may point to how subtle changes in the brain’s circuitry dictate differences in behavior between males and females.
“While we know that human behavior is influenced by numerous factors, including cultural and social norms, these findings point to basic biological mechanisms that may not only help explain some differences in behavior between males and females, but why different sexes may be more susceptible to certain neurological disorders,” said Douglas Portman, Ph.D., an associate professor in the Department of Biomedical Genetics and Center for Neural Development and Disease at the University of Rochester and lead author of the study.
The findings were made in experiments involving C. elegans, a microscopic roundworm that has long been used by researchers to understand fundamental mechanisms in biology. Many of the discoveries made using C. elegans apply throughout the animal kingdom and this research has led to a broader understanding of human biology. In fact, three Nobel Prizes in medicine and chemistry have been awarded for discoveries involving C. elegans.
C. elegans is particularly useful in the study of the nervous system and scientists understand in great detail the development, function, and multiple connections of its entire neural network.
The study published today focuses on the activity of a single pair of neurons found in C. elegans – called AWA – that control smell. Smell, along with taste and touch, are critical sensory factors that dictate how C. elegans understands and navigates its environment, including finding food, avoiding danger, and locating a mate.
There are two sexes of C. elegans, males and hermaphrodites. Though the hermaphrodites are able to self-fertilize, they are also mating partners for males, and are considered to be modified females.
It has been previously observed that males and hermaphrodites act differently when exposed to food. If placed at a food source, the hermaphrodites tend to stay there. Males, however, will leave food source and “wander” – scientist believe they do this because they are in search of a mate.
The Rochester researchers discovered that the sensory mechanisms – called chemoreceptors – of the AWA neurons were regulated by the sexual identity of these cells, which, in turn, controls the expression of a receptor called ODR-10. These receptors bind to a chemical scent that is given off by food and other substances.
In hermaphrodites, more of the ODR-10 receptors are produced, making the worms more sensitive – and thereby attracted – to the presence of food. In males, fewer of these receptors are active, essentially suppressing their ability – and perhaps desire – to find food. However, when males were deprived of food, they produced dramatically higher levels of this receptor, allowing them to temporarily focus on finding food.
To confirm the role of these genetic differences between the sexes on behavior, the researchers designed a series of experiments in which they observed the activity of C. elegans when placed in a petri-dish and confronted with the option to either feed or go in search of a mate. The hermaphrodites were place in the center of the dish at a food source and, as expected, they stayed put.
The males were placed in their own individual food sources at the periphery of the dish. As a further obstacle between the males and their potential mates, an additional ring of food surrounded the hermaphrodites in the center of the dish. The males in the experiment consisted of two categories, one group with a normal genetic profile and another group that had been engineered by the researchers to overexpress the ODR-10 receptor, essentially making them more sensitive to the smell of food.
The researchers found that the normal worms left their food source and eventually made their way to the center of the dish where they mated with the hermaphrodites. The genetically engineered males were less successful at finding a mate, presumably because they were more interested in feeding. By examining the genetic profile of the resulting offspring, the scientists observed that the normal males out-produced the genetically engineered males by 10 to one.
In separate experiments, the researchers were also able to modify the behavior of the hermaphrodites by suppressing the ODR-10 receptors, causing them to act like males and abandon their food source.
“These findings show that by tuning the properties of a single cell, we can change behavior,” said Portman. “This adds to a growing body of evidence that sex-specific regulation of gene expression may play an important role in neural plasticity and, consequently, influence differences in behaviors – and in disease susceptibility – between the sexes.”
(Source: urmc.rochester.edu)
(Image caption: A consensus shape for the calcium ion channel in the worm’s pain receptor nerve that was reached by computer modeling. Credit: Damian van Rossum and Andriy Anishkin, Duke University)
Surprising New Role for Calcium in Sensing Pain
When you accidentally touch a hot oven, you rapidly pull your hand away. Although scientists know the basic neural circuits involved in sensing and responding to such painful stimuli, they are still sorting out the molecular players.
Duke researchers have made a surprising discovery about the role of a key molecule involved in pain in worms, and have built a structural model of the molecule. These discoveries, described Sept. 2 in Nature Communications, may help direct new strategies to treat pain in people.
In humans and other mammals, a family of molecules called TRP ion channels plays a crucial role in nerve cells that directly sense painful stimuli. Researchers are now blocking these channels in clinical trials to evaluate this as a possible treatment for various types of pain.
The roundworm Caenorhabditis elegans also expresses TRP channels — one of which is called OSM-9 — in its single head pain-sensing neuron (which is similar to the pain-sensing nerve cells for the human face). OSM-9 is not only vital for detecting danger signals in the tiny worms, but is also a functional match to TRPV4, a mammalian TRP channel involved in sensing pain.
In the new study, researchers created a series of genetic mutant worms in which parts of the OSM-9 channel were disabled or replaced and then tested the engineered worms’ reactions to overly salty solution, which is normally aversive and painful.
Specifically, the mutant worms had alterations in the pore of the OSM-9 channels in their pain-sensing neuron, which gets fired up upon channel activation to allow calcium and sodium to flow into the neuron. That, in turn, was thought to switch on the neural circuit that encodes rapid withdrawal behavior — like pulling the finger from the stove.
“People strongly believed that calcium entering the cell through the TRP channel is everything in terms of cellular activation,” said lead author Wolfgang Liedtke, M.D., Ph.D., an associate professor of neurology, anesthesiology and neurobiology at Duke University School of Medicine and an attending physician in the Duke Pain Clinics, where he sees patients with chronic head-neck and face-pain.
With then-graduate student Amanda Lindy, “we wanted to systemically mutagenize the OSM-9 pore and see what we could find in the live animal, in its pain behavior,” Liedtke said.
To the group’s surprise, changing various bits of OSM-9’s pore did not change most of the mutant worms’ reactions to the salty solution. However, these mutations did affect the flow of calcium into the cell. The disconnect they saw suggested the calcium was not playing a direct role in the worms’ avoidance of danger signals.
Calcium has been thought to be indispensable for pain behavior — not only in worms’ channels but in pain-related TRP channels in mammals. So results from the engineered OSM-9 mutant worms will change a central concept for the understanding of pain, Liedtke said.
To see whether calcium might instead play a role in the worms’ ability to adapt to repeated painful stimuli, the group then repeatedly exposed pore-mutant worms to the aversive and pain stimuli.
After the tenth trial, a normal worm becomes less sensitive to high salt. But one mutant worm with a minimal change to one specific part of its OSM-9 pore — altered so that calcium no longer entered but sodium did — was just as sensitive on the tenth trial as on the first.
The results confirmed that calcium flow through the channel makes the worms more adaptable to painful stimuli; it helps them cope with the onslaught by desensitizing them. This could well represent a survival advantage, Liedtke said.
To put the findings into a structural context, Liedtke collaborated with computational protein scientists Damian van Rossum and Andriy Anishkin from Penn State University, who built a structural model of OSM-9 that was based on established structures of several of the channel’s relatives, including the recently resolved structure of TRPV1, the molecule that senses pain caused by heat and hot chili peppers.
The team was then able to visualize the key parts of the OSM-9 pore in the context of the entire channel. They understood better how the pore holds its shape and allows sodium and calcium to pass.
Liedtke said that understanding this structure could be a great help in designing compounds that will not completely block the channel but will just prevent calcium from entering the cell. Although calcium helps desensitize worms to painful stimuli in the near term, it might set up chronic, pathological pain circuits in the long term, Liedtke said.
So, as a next step, the group plans to assess the longer-term effects calcium flow has in pain neurons. For example, calcium could change the expression of particular genes in the sensory neuron. And such gene expression changes could underlie chronic, pathologic pain.
“We assume, and so far the evidence is quite good, that chronic, pathological pain has to do with people’s genetic switches in their sensory system set in the wrong way, long term. That’s something our new worm model will now allow us to approach rationally by experimentation,” Liedtke said.
Scientists Uncover Navigation System Used by Cancer, Nerve Cells
Duke University researchers have found a ”roving detection system” on the surface of cells that may point to new ways of treating diseases like cancer, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).
The cells, which were studied in nematode worms, are able to break through normal tissue boundaries and burrow into other tissues and organs — a crucial step in many normal developmental processes, ranging from embryonic development and wound-healing to the formation of new blood vessels.
But sometimes the process goes awry. Such is the case with metastatic cancer, in which cancer cells spread unchecked from where they originated and form tumors in other parts of the body.
“Cell invasion is one of the most clinically relevant yet least understood aspects of cancer progression,” said David Sherwood, an associate professor of biology at Duke.
Sherwood is leading a team that is investigating the molecular mechanisms that control cell invasion in both normal development and cancer, using a one-millimeter worm known as C. elegans.
At one point in C. elegans development, a specialized cell called the anchor cell breaches the dense, sheet-like membrane that separate the worm’s uterus from its vulva, opening up the worm’s reproductive tract.
Anchor cells can’t see, so they need some kind of signal to tell them where to break through. In a 2009 study, Sherwood and colleagues discovered that an extracellular cue called netrin orients the anchor cell so that it invades in the right direction.
In a new study appearing Aug. 25 in the Journal of Cell Biology, the team shows how receptors on the invasive cells essentially rove around the cell membrane ”hunting” for the missing netrin signal that will guide the cell to the correct location.
The researchers used a video camera attached to a powerful microscope to take time-lapse movies of the slow movement of the C. elegans anchor cell during its invasion (Figure 1, Figure 2).
Their time-lapse analyses reveal that when netrin production is blocked, netrin receptors on the surface of the anchor cell periodically cluster, disperse and reassemble in a different region of the cell membrane. The receptors cluster alongside patches of actin filaments — thin flexible fibers that help cells change shape and form invasive protrusions –- that pop up in each new spot.
“It’s kind of like a missile detection system,” Sherwood said.
Rather than the whole cell having to move around, its receptors move around on the outside of the cell until they get a signal. Once the receptors locate the netrin signal, they stabilize in the region of the cell membrane that is closest to the source of the signal.
The findings redefine decades-old ideas about how the cell’s navigation system works. “Cells don’t just passively respond to the netrin signal — they’re actively searching for it,” Sherwood said.
Given that netrin has been found to promote cell invasion in some of the most lethal cancers, the findings could lead to new treatment strategies. Disrupting the cell’s netrin detection system, for example, could prevent cancer cells from finding their way to the bloodstream or the lymphatic system and stop them from metastasizing, or becoming invasive and spreading throughout the body.
“One of the things we’re gearing up to do next are drug screens with our collaborators to see if we can block this detection system during invasion,” Sherwood said.
Scientists have also known for years that netrin plays a key role in wiring the brain and nervous system by guiding developing nerve cells as they grow and form connections.
This means the results could also point to new ways of treating neurological disorders like Parkinson’s and ALS and recovering from spinal cord injuries.
Tinkering with the cell’s netrin detection machinery, for example, may make it possible to encourage damaged cells in the central nervous system — which normally have limited ability to regenerate — to regrow.
(Source: today.duke.edu)
Neurons at work
Film editors play a critical role by helping shape raw footage into a narrative. Part of the challenge is that their work can have a profound impact on the finished product — with just a few cuts in the wrong places, comedy can become tragedy, or vice versa.
A similar process, “alternative splicing,” is at work inside the bodies of billions of creatures — including humans. Just as a film editor can change the story with a few cuts, alternative splicing allows cells to stitch genetic information into different formations, enabling a single gene to produce up to thousands of different proteins.
Harvard scientists say they’ve now been able to observe that process within the nervous system of a living creature.
Mutation stops worms from getting drunk
Neuroscientists at The University of Texas at Austin have generated mutant worms that do not get intoxicated by alcohol, a result that could lead to new drugs to treat the symptoms of people going through alcohol withdrawal.
The scientists accomplished this feat by inserting a modified human alcohol target into the worms, as reported this week in The Journal of Neuroscience.
"This is the first example of altering a human alcohol target to prevent intoxication in an animal," says corresponding author, Jon Pierce-Shimomura, assistant professor in the university’s College of Natural Sciences and Waggoner Center for Alcohol and Addiction Research.
An alcohol target is any neuronal molecule that binds alcohol, of which there are many.
One important aspect of this modified alcohol target, a neuronal channel called the BK channel, is that the mutation only affects its response to alcohol. The BK channel typically regulates many important functions including activity of neurons, blood vessels, the respiratory tract and bladder. The alcohol-insensitive mutation does not disrupt these functions at all.
"We got pretty lucky and found a way to make the channel insensitive to alcohol without affecting its normal function," says Pierce-Shimomura.
The scientists believe the research has potential application for treating people addicted to alcohol.
"Our findings provide exciting evidence that future pharmaceuticals might aim at this portion of the alcohol target to prevent problems in alcohol abuse disorders," says Pierce-Shimomura. "However, it remains to be seen which aspects of these disorders would benefit."
Unlike drugs such as cocaine, which have a specific target in the nervous system, the effects of alcohol on the body are complex and have many targets across the brain. The various other aspects of alcohol addiction, such as tolerance, craving and the symptoms of withdrawal, may be influenced by different alcohol targets.
The worms used in the study, Caenorhabditis elegans, model intoxication well. Alcohol causes the worms to slow their crawling with less wriggling from side to side. The intoxicated worms also stop laying eggs, which build up in their bodies and can be easily counted.
Unfortunately, C. elegans are not as ideal for studying the other areas of alcohol addiction, but mice make an excellent model. The modified human BK channel used in the study, which is based on a mutation discovered by lead author and graduate student Scott Davis, could be inserted into mice. These modified mice would allow scientists to investigate whether this particular alcohol target also affects tolerance, craving and other symptoms relevant to humans.
Pierce-Shimomura speculated that their research could even be used to develop a ‘James Bond’ drug someday, which would enable a spy to drink his opponent under the table, without getting drunk himself. Such a drug could potentially be used to treat alcoholics, since it would counteract the intoxicating and potentially addicting effects of the alcohol.
Illuminating neuron activity in 3-D
Researchers at MIT and the University of Vienna have created an imaging system that reveals neural activity throughout the brains of living animals. This technique, the first that can generate 3-D movies of entire brains at the millisecond timescale, could help scientists discover how neuronal networks process sensory information and generate behavior.
The team used the new system to simultaneously image the activity of every neuron in the worm Caenorhabditis elegans, as well as the entire brain of a zebrafish larva, offering a more complete picture of nervous system activity than has been previously possible.
“Looking at the activity of just one neuron in the brain doesn’t tell you how that information is being computed; for that, you need to know what upstream neurons are doing. And to understand what the activity of a given neuron means, you have to be able to see what downstream neurons are doing,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and one of the leaders of the research team. “In short, if you want to understand how information is being integrated from sensation all the way to action, you have to see the entire brain.”
The new approach, described May 18 in Nature Methods, could also help neuroscientists learn more about the biological basis of brain disorders. “We don’t really know, for any brain disorder, the exact set of cells involved,” Boyden says. “The ability to survey activity throughout a nervous system may help pinpoint the cells or networks that are involved with a brain disorder, leading to new ideas for therapies.”
Boyden’s team developed the brain-mapping method with researchers in the lab of Alipasha Vaziri of the University of Vienna and the Research Institute of Molecular Pathology in Vienna. The paper’s lead authors are Young-Gyu Yoon, a graduate student at MIT, and Robert Prevedel, a postdoc at the University of Vienna.
High-speed 3-D imaging
Neurons encode information — sensory data, motor plans, emotional states, and thoughts — using electrical impulses called action potentials, which provoke calcium ions to stream into each cell as it fires. By engineering fluorescent proteins to glow when they bind calcium, scientists can visualize this electrical firing of neurons. However, until now there has been no way to image this neural activity over a large volume, in three dimensions, and at high speed.
Scanning the brain with a laser beam can produce 3-D images of neural activity, but it takes a long time to capture an image because each point must be scanned individually. The MIT team wanted to achieve similar 3-D imaging but accelerate the process so they could see neuronal firing, which takes only milliseconds, as it occurs.
The new method is based on a widely used technology known as light-field imaging, which creates 3-D images by measuring the angles of incoming rays of light. Ramesh Raskar, an associate professor of media arts and sciences at MIT and an author of this paper, has worked extensively on developing this type of 3-D imaging. Microscopes that perform light-field imaging have been developed previously by multiple groups. In the new paper, the MIT and Austrian researchers optimized the light-field microscope, and applied it, for the first time, to imaging neural activity.
With this kind of microscope, the light emitted by the sample being imaged is sent through an array of lenses that refracts the light in different directions. Each point of the sample generates about 400 different points of light, which can then be recombined using a computer algorithm to recreate the 3-D structure.
“If you have one light-emitting molecule in your sample, rather than just refocusing it into a single point on the camera the way regular microscopes do, these tiny lenses will project its light onto many points. From that, you can infer the three-dimensional position of where the molecule was,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research.
Prevedel built the microscope, and Yoon devised the computational strategies that reconstruct the 3-D images.
Aravinthan Samuel, a professor of physics at Harvard University, says this approach seems to be an “extremely promising” way to speed up 3-D imaging of living, moving animals, and to correlate their neuronal activity with their behavior. “What’s very impressive about it is that it is such an elegantly simple implementation,” says Samuel, who was not part of the research team. “I could imagine many labs adopting this.”
Neurons in action
The researchers used this technique to image neural activity in the worm C. elegans, the only organism for which the entire neural wiring diagram is known. This 1-millimeter worm has 302 neurons, each of which the researchers imaged as the worm performed natural behaviors, such as crawling. They also observed the neuronal response to sensory stimuli, such as smells.
The downside to light field microscopy, Boyden says, is that the resolution is not as good as that of techniques that slowly scan a sample. The current resolution is high enough to see activity of individual neurons, but the researchers are now working on improving it so the microscope could also be used to image parts of neurons, such as the long dendrites that branch out from neurons’ main bodies. They also hope to speed up the computing process, which currently takes a few minutes to analyze one second of imaging data.
The researchers also plan to combine this technique with optogenetics, which enables neuronal firing to be controlled by shining light on cells engineered to express light-sensitive proteins. By stimulating a neuron with light and observing the results elsewhere in the brain, scientists could determine which neurons are participating in particular tasks.
How a small worm may help the fight against Alzheimer’s
Scientists at the Max Planck Institute for Biology of Ageing in Cologne have found that a naturally occurring molecule has the ability to enhance defense mechanisms against neurodegenerative diseases. Feeding this particular metabolite to the small round worm Caenorhabditis elegans, helps clear toxic protein aggregates in the body and extends life span.
During ageing, proteins in the human body tend to aggregate. At a certain point, protein aggregation becomes toxic, overloads the cell, and thus prevents it from maintaining normal function. Damage can occur, particularly in neurons, and may result in neurodegenerative diseases like Alzheimer’s, Parkinson’s or Huntington’s disease. By studying model organisms like Caenorhabditis elegans, scientists have begun to uncover the mechanisms underlying neurodegeneration, and thus define possible targets for both therapy and prevention of those diseases. “Although we cannot measure dementia in worms“, explains Martin Denzel of the Max Planck Institute for Biology of Ageing, “we can observe proteins that we also know from human diseases like Alzheimer’s to be toxic by measuring effects on neuromuscular function. This gives us insight into how Alzheimer actually progresses on the molecular level“.
Now, the scientists Martin Denzel, Nadia Storm, and Max Planck Director Adam Antebi have discovered that a substance called N-acetylglucosamine apparently stimulates the body’s own defense mechanism against such toxicity. This metabolite occurs naturally in the organism. If it is additionally fed to the worm, “we can achieve very dramatic benefits“, says Denzel. “It is a broad-spectrum effect that alleviates protein toxicity in Alzheimer’s, Parkinson’s and Huntington’s disease models in the worm, and it even extends their life span.“
This molecule apparently plays a crucial role in quality control mechanisms that keep the body healthy. It helps the organism to clear toxic levels of protein aggregation, both preventing aggregates from forming and clearing already existing ones. As a result, onset of paralysis is delayed in models of neurodegeneration - How exactly the molecule achieves this effect is yet to be uncovered. “And we still don’t know whether it also works in higher animals and humans“, says Antebi. “But as we also have these metabolites in our cells, this gives good reason to suspect that similar mechanisms might work in humans.”
Forgetting Is Actively Regulated
In order to function properly, the human brain requires the ability not only to store but also to forget: Through memory loss, unnecessary information is deleted and the nervous system retains its plasticity. A disruption of this process can lead to serious mental disorders. Basel scientists have now discovered a molecular mechanism that actively regulates the process of forgetting. The renowned scientific journal “Cell” has published their results.
The human brain is build in such a way, that only necessary information is stored permanently - the rest is forgotten over time. However, so far it was not clear if this process was active or passive. Scientists from the transfaculty research platform Molecular and Cognitive Neurosciences (MCN) at the University of Basel have now found a molecule that actively regulates memory loss. The so-called musashi protein is responsible for the structure and function of the synaptic connections of the brain, the place where information is communicated from one neuron to the next.
Using olfactory conditioning, the researchers Attila Stetak and Nils Hadziselimovic first studied the learning abilities of genetically modified ringworms (C. elegans) that were lacking the musashi protein. The experiments showed that the worms exhibited the same learning skills as unmodified animals. However, with extended duration of the experiment, the scientists discovered that the mutants were able to remember the new information much better. In other words: The genetically modified worms lacking the musashi protein were less forgetful.
Forgetting is no coincidence
Further experiments showed that the protein inhibits the synthesis of molecules responsible for the stabilization of synaptic connections. This stabilization seems to play an important role in the process of learning and forgetting. The researchers identified two parallel mechanisms: One the one hand, the protein adducin stimulates the growth of synapses and therefore also helps to retain memory; on the other hand, the musashi protein actively inhibits the stabilization of these synapses and thus facilitates memory loss. Therefore, it is the balance between these two proteins that is crucial for the retention of memories.
Forgetting is thus not a passive but rather an active process and a disruption of this process may result in serious mental disorders. The musashi protein also has interesting implications for the development of drugs trying to prevent abnormal memory loss that occurs in diseases such as Alzheimer’s. Further studies on the therapeutic possibilities of this discovery will be done.
Age no obstacle to nerve cell regeneration
In aging worms at least, it is insulin, not Father Time, that inhibits a motor neuron’s ability to repair itself — a finding that suggests declines in nervous system health may not be inevitable.
All organisms show a declining ability to regenerate damaged nervous systems with age, but the study appearing in the Feb. 5 issue of the journal Neuron suggests this deficit is not due to the ravages of time.
“The nervous system regulates its own response to age, separately from what happens in the rest of the body,” said Marc Hammarlund, assistant professor of genetics and senior author of the new study. “By manipulating the insulin pathway, we can make animals that live longer but have nervous systems that age normally, or conversely, we can make animals that die at a normal age but have a young nervous system.”
Alexandra Byrne, postdoctoral associate in genetics and lead author of the study, identified two genetic pathways that regulate insulin activity and are responsible for age-related declines in a worm’s ability to regenerate neuronal axons, or connective branches. The team pinpointed two other pathways that also regulate a neuron’s ability to regenerate, but that have no connection to the age of the worm.
The worm C. elegans is a well-established model to study the genetics of aging, and manipulation of the family of genes that regulate insulin activity has been shown to dramatically increase lifespan of the organism. The new study reveals that insulin signaling is also directly affecting the nervous system.
“We hope to understand how different pathways coordinately regulate neuronal aging, and more specifically, how to entice an aged neuron to regenerate after injury,” Byrne said.
“The hope is to increase healthspan, not just lifespan,” Hammarlund said.
New compound for slowing the aging process can lead to novel treatments for brain diseases
A successful joint collaboration between researchers at the Hebrew university of Jerusalem and the startup company TyrNovo may lead to a potential treatment of brain diseases. The researchers found that TyrNovo’s novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. This is a first and important step towards the development of future drugs for the treatment of various neurodegenerative maladies.
Human neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases share two key features: they stem from toxic protein aggregation and emerge late in life. The common temporal emergence pattern exhibited by these maladies proposes that the aging process negatively regulates protective mechanisms that prevent their manifestation early in life, exposing the elderly to disease. This idea has been the major focus of the work in the laboratory of Dr. Ehud Cohen of the Department of Biochemistry and Molecular Biology, at the Institute for Medical Research Israel-Canada in the Hebrew University of Jerusalem’s Faculty of Medicine.
Cohen’s first breakthrough in this area occurred when he discovered, working with worms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer’s disease. Later, he found that the inhibition of this signaling route also protected Alzheimer’s-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.
Dr. Hadas Reuveni, the CEO of TyrNovo, a startup company formed for the clinical development of NT219, and Prof. Alexander Levitzki from the Department of Biological Chemistry at the Hebrew University, with their research teams, discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.
Now, in a fruitful collaboration Dr. Cohen and Dr. Reuveni, together with Dr. Cohen’s associates Tayir El-Ami and Lorna Moll, have demonstrated that NT219 efficiently inhibits IGF1 signaling, in both worms and human cells. The inhibition of this signaling pathway by NT219 protected worms from toxic protein aggregation that in humans is associated with the development of Alzheimer’s or Huntington’s disease.
The discoveries achieved during this project, which was funded by the Rosetrees Trust of Britain, were published this week in the journal Aging Cell (“A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity”). The findings strengthen the notion that the inhibition of the IGF1 signaling pathway has a therapeutic potential as a treatment for neurodegenerative disorders. They also point at NT219 as the first compound that provides protection from neurodegeneration-associated toxic protein aggregation through a selective manipulation of aging.
Cohen, Reuveni and Levitzki have filed a patent application that protects the use of NT219 as a treatment for neurodegenerative maladies through Yissum, the technology transfer company of the Hebrew University. Dr. Gil Pogozelich, chairman of Goldman Hirsh Partners Ltd., which holds the controlling interest in TyrNovo, says that he sees great importance in the cooperation on this project with the Hebrew University, and that TyrNovo represents a good example of how scientific and research initiatives can further health care together with economic benefits.
Recently, Dr. Cohen’s laboratory obtained an ethical approval to test the therapeutic efficiency of NT219 as a treatment in Alzheimer’s-model mice, hoping to develop a future treatment for hitherto incurable neurodegenerative disorders.