Posts tagged neurons
Articles and news from the latest research reports.
Fatheads: How neurons protect themselves against excess fat
We’re all fatheads. That is, our brain cells are packed with fat molecules, more of them than almost any other cell type. Still, if the brain cells’ fat content gets too high, they’ll be in trouble. In a recent study in mice, researchers at Johns Hopkins pinpointed an enzyme that keeps neurons’ fat levels under control, and may be implicated in human neurological diseases. Their findings are published in the May 2013 issue of Molecular and Cellular Biology.
"There are known connections between problems with how the body’s cells process fats and neurodegenerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis," says Michael Wolfgang, Ph.D., an assistant professor in the Department of Biological Chemistry at the Johns Hopkins University School of Medicine’s Institute for Basic Biomedical Sciences. "Now we’ve taken a step toward better understanding that connection by identifying an enzyme that lets neurons get rid of excess fat that would otherwise be toxic."
Wolfgang says one clue to the reason for the neurodegeneration/fat-processing connection is that neurons, unlike most cells in the body, seemingly can’t break down fats for energy. Instead, brain cells use fats for tasks such as building cell membranes and communicating information. At the same time, he says, they must prevent the buildup of unneeded fats. Neurons’ fat-loss strategy is rooted in the fact that a fat molecule attached to a chemical group called coenzyme A will be trapped inside the cell, while the coenzyme A-free version can easily cross the cell membrane and escape. With this in mind, Wolfgang, along with colleagues Jessica Ellis, Ph.D., and G. William Wong, Ph.D., focused their study on an enzyme, called ACOT7, which is plentiful in the brain and lops coenzyme A off of certain fat molecules.
The team created mice with a non-working gene for ACOT7 and compared them with normal mice. The scientists saw no obvious differences between the two types of mice as long as they had ready access to food, Wolfgang says. But when food was taken away overnight, so that the mice’s cells would start to break down their fat stores and release fat molecules into the bloodstream for use as energy, ACOT7’s role began to emerge. While the normal fasting mice were merely hungry, the mice lacking ACOT7 had poor coordination, a sign of neurodegeneration. More differences emerged when the researchers dissected the mice; most strikingly, the livers of mice missing ACOT7 were “stark white” with excess fat, Wolfgang says.
Wolfgang cautions that his group’s results are not quite a smoking gun for ACOT7’s involvement in human neurological disease, but says they add to existing circumstantial evidence pointing in that direction. He notes that a special diet that changes the levels of fats and sugars in the bloodstream – the so-called ketogenic diet – can prevent seizures in epileptics; in addition, one study found that patients with epilepsy have less of the ACOT7 enzyme than healthy people.
"We think ACOT7’s purpose is to protect neurons from toxicity and death by allowing excess fat to escape the cells," Ellis says. "Our next step will be to see whether this enzyme does indeed play a role in human neurological disease."
(Image: Courtesy of Sabrina Diano)
Study finds that hot and cold senses interact
A study from the University of North Carolina School of Medicine offers new insights into how the nervous system processes hot and cold temperatures. The research led by neuroscientist Mark J. Zylka, PhD, associate professor of cell biology and physiology, found an interaction between the neural circuits that detect hot and cold stimuli: cold perception is enhanced when nerve circuitry for heat is inactivated.
“This discovery has implications for how we perceive hot and cold temperatures and for why people with certain forms of chronic pain, such as neuropathic pain, or pain arising as direct consequence of a nervous system injury or disease, experience heightened responses to cold temperatures,” says Zylka, a member of the UNC Neuroscience Center.
The study also has implications for why a promising new class of pain relief drugs known as TRPV1 antagonists (they block a neuron receptor protein) cause many patients to shiver and “feel cold” prior to the onset of hyperthermia, an abnormally elevated body temperature. Enhanced cold followed by hyperthermia is a major side effect that has limited the use of these drugs in patients with chronic pain associated with multiple sclerosis, cancer, and osteoarthritis.
Zylka’s research sheds new light on how the neural circuits that regulate temperature sensation bring about these responses, and could suggest ways of reducing such side-effects associated with TRPV1 antagonists and related drugs.
The research was selected by the journal Neuron as cover story for the April 10, 2013 print edition and was available in the April 4, 2013 advanced online edition.
This new study used cutting edge cell ablation technology to delete the nerve circuit that encodes heat and some forms of itch while preserving the circuitry that sense cold temperatures. This manipulation results in animals that were practically “blind” to heat, meaning they could no longer detect hot temperatures, Zylka explains. “Just like removing heat from a room makes us feel cold (such as with an air conditioner), removing the circuit that animals use to sense heat made them hypersensitive to cold. Physiological studies indicated that these distinct circuits regulate one another in the spinal cord.”
TRPV1 is a receptor for heat and is found in the primary sensory nerve circuit that Zylka studied. TRPV1 antagonists make patients temporarily blind to heat, which Zylka speculates is analogous to what happened when his lab deleted the animals’ circuit that detects heat: cold hypersensitivity.
Zylka emphasizes that future studies will be needed to confirm that TRPV1 antagonists affect cold responses in a manner similar to what his lab found with nerve circuit deletion.
Fruit flies may have more individuality and personality than we imagine.
And it might all be down to a bit of genetic shuffling in nerve cells that makes every fly brain unique, suggest Oxford University scientists.
Their new study has found that small genetic elements called ‘transposons’ are active in neurons in the fly brain. Transposons are also known as 'jumping genes', as these short scraps of DNA have the ability to move, cutting themselves out from one position in the genome and inserting themselves somewhere else.
The inherent randomness of the process is likely to make every fly brain unique, potentially providing behavioural individuality – or ‘fly personality’. So says Professor Scott Waddell, who led the work at the University of Oxford Centre for Neural Circuits and Behaviour: ‘We have known for some time that individual animals that are supposed to be genetically identical behave differently.
'The extensive variation between fly brains that this mechanism could generate might demystify why some behave while others misbehave,' he suggests.
The Oxford researchers, along with US colleagues at the University of Massachusetts Medical School and Howard Hughes Medical Institute, were able to deep-sequence the DNA from small numbers of nerve cells in the brains of Drosophila fruit flies.
They identified many transposons that were inserted in a number of important memory-related genes. Whether this is detrimental or advantageous to the fly remains an open question, the researchers say.
Scott Waddell notes that neural transposition has been described in rodent and human brains, and transposons have historically been considered to be problematic parasites. New insertions of transposons can on occasion disrupt genes (as was found in this study), and transposons have been associated to some human disorders such as schizophrenia.
However, it is also possible that organisms have harnessed transposition to generate variation within cells, and by extension create variation between individual animals that may turn out to be favourable.
Scott Waddell wants next to determine whether neural transposition provides an explanation for variation in fruit fly behaviour by finding ways of halting the process in flies in his lab.
How do we hear? More specifically, how does the auditory center of the brain discern important sounds – such as communication from members of the same species – from relatively irrelevant background noise? The answer depends on the regulation of sound by specific neurons in the auditory cortex of the brain, but the precise mechanisms of those neurons have remained unclear. Now, a new study from the Perelman School of Medicine at the University of Pennsylvania has isolated how neurons in the rat’s primary auditory cortex (A1) preferentially respond to natural vocalizations from other rats over intentionally modified vocalizations (background sounds). A computational model developed by the study authors, which successfully predicted neuronal responses to other new sounds, explained the basis for this preference. The research is published in the Journal of Neurophysiology.
Rats communicate with each other mostly through ultrasonic vocalizations (USVs) beyond the range of human hearing. Although the existence of these USV conversations has been known for decades, “the acoustic richness of them has only been discovered in the last few years,” said senior study author Maria N. Geffen, PhD, assistant professor of Otorhinolaryngology: Head and Neck Surgery at Penn. That acoustical complexity raises questions as to how the animal brain recognizes and responds to the USVs. “We set out to characterize the responses of neurons to USVs and to come up with a model that would explain the mechanism that makes these neurons preferentially responsive to these relevant sounds.”
Geffen and her colleagues obtained recordings of USVs from two rats kept together in a cage, then played the recordings to a separate group of male rats, while their neuronal responses were acquired and recorded. The researchers also used USV recordings that were modified in several ways, such as having background sounds filtered out and being played backwards and at different speeds to mimic unimportant background noise. “We found that neurons in the auditory cortex respond strongly and selectively to the original ultrasonic vocalizations and not the transformed versions we created,” says Geffen.
Using the data collected on the responses of A1 neurons to various USVs, the researchers developed a computational model that could predict the activity of an individual neuron based on the pitch and duration of the USV. Geffen observes that “the details of their responses could be predicted with high accuracy.” It was possible to determine which aspects of the acoustic input best drove individual neurons. Remarkably, it turned out that the acoustic parameters that worked best in driving the neuronal responses corresponded to the statistics of the natural vocalizations rats produce.
The work makes clear for the first time, says Geffen, “the mechanisms of how the auditory system picks out behaviorally relevant sounds, such as same species communication signals, and processes them more effectively than less relevant sounds. This information is fundamental in understanding how sound perception helps animals survive. We conclude that neurons in the auditory cortex are specialized for processing and efficiently responding to natural and behaviorally relevant sounds.”
(Image: National Institute on Deafness and Other Communication)
Separate lives: Neuronal and organismal lifespans decoupled
Replicative aging (also known as replicative senescence) causes mammalian cells to undergo a process of growth arrest dependent on telomeres (the shortening of repeated sequences at the ends of chromosomes). Neurons, on the other hand, are exempt from aging, and so the question of their actual lifespan has remained unanswered. Recently, however, scientists at the University of Pavia and the University of Turin demonstrated that neuronal lifespan is not limited by the organism’s maximum lifespan but, remarkably, continues when transplanted in a longer-living host. The researchers accomplished this by transplanting embryonic mouse cerebellar precursors into the developing brain of longer-living rats, in which the grafted mouse neurons survived for up to three years – twice the average lifespan of the donor mice.
Dr. Lorenzo Magrassi discussed the challenges he and his colleagues, Dr. Ketty Leto and Dr. Ferdinando Rossi, encountered in their research. “Cell transplantation into the developing rat brain is a technique that was originally developed by us and other research groups in the early nineties of the last century,” Magrassi tells Medical Xpress. “In recent years, we improved the protocol that, now standardized, allows reliable implantation rates with good survival rates.” While not all implanted embryos develop into adult animals carrying a viable transplant, Magrassi adds, the percentage of those that do is sufficient to plan a long-term survival experiment involving roughly 100 such successfully-born animals.
In addressing these challenges, Magrassi says that together with the intrinsic bonus of studying cells inside the nervous system, which is immunoprivileged, they transplanted cells before development of the thymus (a specialized organ of the immune system) was complete. The latter can help induce immunological tolerance in the host to the engrafted cells.
One remaining question is if their research can potentially be extended to determine whether or not a maximum lifespan exists for any postmitotic mammalian cells – Including neurons. “Similar techniques can, in principle, be extended to other organs containing perennial cells,” Magrassi notes, “but we don’t have direct experience with injecting cells into organs outside of the central nervous system.” Since the central nervous system is privileged compared to other organs that are more prone to immunological surveillance and attack, a major problem when transferring their experimental paradigm to other organs, he explains, could be an increase in immunological problems.
The scientists say their results suggest that neuronal survival and aging are coincidental but separable processes, thus increasing the hope that extending organismal lifespan by dietary, behavioral, and pharmacologic interventions will not necessarily result in a neuronally depleted brain. “Even after taking into account the obvious species differences, our results in rodents can be extrapolated by analogy to humans and other longer-living species where this sort of experiment is impossible,” Magrassi explains. “Our findings suggest that extending life by extending average organismal lifespan – a hallmark of all technologically advanced societies – will not necessarily result in neuron-impoverished brains well before the longer-living individual dies.” This bodes well for those studying life extension: Their efforts are not intrinsically futile, Magrassi notes, because in the absence of pathology, prolonging life span does not necessarily mean dementia due to widespread loss of neurons, as many people still think. “Roughly speaking,” Magrassi illustrates, “if the average lifespan of humans is now 80 years, our results suggest that at ages up to 160 years our neurons can survive if not hit by specific insults.
That said, however, Magrassi acknowledges that neuronal death is not the only effect of normal aging in the brain. “For example,” he illustrates, “cerebellar neurons – which in term of synaptic loss behave like the majority of neurons in the brain – show a substantial loss of dendritic branches, spines and synapses in normal aging. In our research, we studied transplanted mouse Purkinje cells to determine if their spine density decreased with time at the same rate of Purkinje cells in the mouse or in the rat.” Purkinje cells are large GABAergic (that is, gamma-Aminobutyric acid-producing) neurons, with many branching extensions, found in the cortex of the cerebellum. “The results of our experiments indicate that age-related progressive spine loss of grafted mouse Purkinje cells follows a slower pace, typical of the longer living rat, thus reaching absolute levels of spine loss comparable to those observed in aged mice at much longer survival times that are typical of the rat.”
Moreover, Magrassi adds that their experiments clearly show that by escaping immunological rejection, transplanted neurons can survive undisturbed for the entire life of the host. “This has implications for the ongoing discussion of the detrimental effects of immune attacks on transplanted neural cells for therapeutic purposes,”
Moving forward, in order to screen for intra- and extracellular changes that could be responsible for the long term survival of the mouse cells transplanted into rat brains – as well as the slowdown of dendritic spine loss – the team is planning to perform host and transplanted cell microdissection followed by a proteomic approach. “If we discover what factor or factors cause those changes,” Magrassi points out, “we could hopefully then develop more efficient drugs for treating all pathological neurodegenerative conditions in which neurons start to lose synaptic contacts and die well before organismal death – for example, dementia, memory loss and cognitive impairment. Of course,” he adds, “this work is still in progress and the results are preliminary.”
In addition, the scientists are currently testing xenotransplantation using different transgenic mouse strains with altered aging pathways as donors to characterize the pathways that led to their results.
Magrassi sees other areas of research that might benefit from their study. “Knowing that neuronal aging in rodents is not a cell-autonomous process is important not only for neuroscience,” he concludes. “It also has implications for evolutionary biology and epidemiology.”
(Source: medicalxpress.com)
Epilepsy sends differentiated neurons on the run
The smooth operation of the brain requires a certain robustness to fluctuations in its home within the body. At the same time, its extraordinary power derives from an activity structure poised at criticality. In other words, it is highly responsive to many low-threshold events. When forced beyond its comfort zone in parameter space—its operating temperature, electrolytes, sugars, blood gas or even sensory input— the direct result is seizure, coma, or both. It would appear that anything rendered too hot or cold, too concentrated or scarce, precipitates seizure. In those genetically predisposed, or compromised by head trauma, the seizing tends toward full-blown epilepsy. A group in Hamburg, led by Michael Frotscher has been chipping away at the causes of common form a epilepsy, temporal lobe epilepsy (TLE). Their latest research published in the journal, Cerebral Cortex, takes a closer at differentiated neurons in the dentate gyrus of mouse hippocampus. Once thought to be completely immobilized by virtue of their broadly integrated dendritic trees, these neurons are now shown to become migratory once again in direct response to seizure activity.
Genetic predisposition to seizure can come in the form of ongoing chemical or metabolic imbalance due to defects in enzymes, ion channels or receptors. Alternatively it manifests through direct structural defect as a result of a developmental flaw. In slice preparations, Frotscher looked at a particular form of TLE, where the granule cell layer (GCL) in the dentate gyrus is disrupted. The cells there have either failed to migrate along glial scaffolds into a compact layer with clearly defined margins, or aberrant clumps of cells congregate in the wrong places. Seizures secondary to fever have been known to cause this aberrant migration of granule cells, as has a particular kind of mouse mutant known as the reeler mouse.
The catalog of mouse mutants is expansive; it is a veritable library of hopeless monsters. The reeler mutant, known since 1951, has a unique set of issues wherein cells fail to migrate to the right spots in the cerebellum, cortex, and hippocampus. The protein, reelin was later discovered as one of the causes of this particular phenotype. Reelin is an extracellular matrix protein which initially provides scaffolding for neuron migration, and later a fence to fix neurons in place. In mice with mutated reelin protein, cells in all parts of the hippocampus, not just the dentate gyrus are spread out into a broad and diffuse layer.
By injecting kainate (KA), an excitotoxin that predictably results in seizures, into the dentate gyrus, Frotscher biased the granule cells into entering a phase of bursting activity. With their glutamate receptors fully activated by KA, the granule cells fire rapid volleys of spikes followed by deep depolarization periods. Cells that had been fluorescently labeled with GFP and observed with real time video microscopy were also seen to become motile and dispersed. The normal band of granule cells doubled, or tripled, in thickness. Next, Frostcher looked for a link between this response to KA and the reelin protein. Both reelin mRNA and reelin immunoreactivity were found to be reduced in the dentate granule cells that had been dispersed by KA.
Against this tableau of complex responses to KA, is the fact that adult neurogenesis of dentate granule cells occurs within many mammalian species. A narrowly-defined rostral migratory stream normally delivers fresh cells to both the dentate gyrus and olfactory bulb. Application of BrdU, a marker of newly born cells, labeled microglial and astrocytes near the site of injection, but only a few of the granule cells. As an excitotoxin, KA may be expected to kill at least some cells outright, and cause significant dendritic degeneration in many more. An interesting question to ask, is how does KA induce granule cell dispersion despite the dense interconnections with their neighbors?
During KA induced motility, the nucleus was typically observed to translocate within the cell into one of the dendrites, pulling the soma along with it. This process is believed to involve a myosin-dependant forward flow of actin structural protein within the cell. Outside the cell, changes to the reelin matrix appear to be involved as well. One potential mechanism that has emerged is that reelin induces serine phosporylation of cofilin, an actin-associated protein involved in depolymerization. The authors conclude reelin-induced cofilin phosphorylation controls neuronal migration during development, and prevents abnormal motility in the mature brain.
Undoubtedly many mechanisms are involved in the KA-induced seizure and reelin story. Other cell types in the dentate gyrus need to be looked at in closer detail. For example, how reelin expression is regulated, and which cells manufacture it are current areas of study. It is important as well to differentiate between the causes of seizure, and its consequences. On paper they can be neatly packaged concepts but in the real tissue, and in intact animals, they can be anything but.
(Source: medicalxpress.com)
How herpesvirus invades nervous system
Northwestern Medicine scientists have identified a component of the herpesvirus that “hijacks” machinery inside human cells, allowing the virus to rapidly and successfully invade the nervous system upon initial exposure.
Led by Gregory Smith, associate professor in immunology and microbiology at Northwestern University Feinberg School of Medicine, researchers found that viral protein 1-2, or VP1/2, allows the herpesvirus to interact with cellular motors, known as dynein. Once the protein has overtaken this motor, the virus can speed along intercellular highways, or microtubules, to move unobstructed from the tips of nerves in skin to the nuclei of neurons within the nervous system.
This is the first time researchers have shown a viral protein directly engaging and subverting the cellular motor; most other viruses passively hitch a ride into the nervous system.
"This protein not only grabs the wheel, it steps on the gas," says Smith. "Overtaking the cellular motor to invade the nervous system is a complicated accomplishment that most viruses are incapable of achieving. Yet the herpesvirus uses one protein, no others required, to transport its genetic information over long distances without stopping."
Herpesvirus is widespread in humans and affects more than 90 percent of adults in the United States. It is associated with several types of recurring diseases, including cold sores, genital herpes, chicken pox, and shingles. The virus can live dormant in humans for a lifetime, and most infected people do not know they are disease carriers. The virus can occasionally turn deadly, resulting in encephalitis in some.
Until now, scientists knew that herpesviruses travel quickly to reach neurons located deep inside the body, but the mechanism by which they advance remained a mystery.
Smith’s team conducted a variety of experiments with VP1/2 to demonstrate its important role in transporting the virus, including artificial activation and genetic mutation of the protein. The team studied the herpesvirus in animals, and also in human and animal cells in culture under high-resolution microscopy. In one experiment, scientists mutated the virus with a slower form of the protein dyed red, and raced it against a healthy virus dyed green. They observed that the healthy virus outran the mutated version down nerves to the neuron body to insert DNA and establish infection.
"Remarkably, this viral protein can be artificially activated, and in these conditions it zips around within cells in the absence of any virus. It is striking to watch," Smith says.
He says that understanding how the viruses move within people, especially from the skin to the nervous system, can help better prevent the virus from spreading.
Additionally, Smith says, “By learning how the virus infects our nervous system, we can mimic this process to treat unrelated neurologic diseases. Even now, laboratories are working on how to use herpesviruses to deliver genes into the nervous system and kill cancer cells.”
Smith’s team will next work to better understand how the protein functions. He notes that many researchers use viruses to learn how neurons are connected to the brain.
"Some of our mutants will advance brain mapping studies by resolving these connections more clearly than was previously possible," he says.
Riding the exosome shuttle from neuron to muscle
Novel intercellular transportation system may have potential for delivering RNAi and other gene-based therapeutics
Important new research from UMass Medical School demonstrates how exosomes shuttle proteins from neurons to muscle cells where they take part in critical signaling mechanisms, an exciting discovery that means these tiny vehicles could one day be loaded with therapeutic agents, such as RNA interference (RNAi), and directly target disease-carrying cells. The study, published this month in the journal Neuron, is the first evidence that exosomes can transfer membrane proteins that play an important role in cell-to-cell signaling in the nervous system.
“There has been a long-held belief that certain cellular materials, such as integral membrane proteins, are unable to pass from one cell to another, essentially trapping them in the cell where they are made,” said Vivian Budnik, PhD, professor of neurobiology and lead author of the study. “What we’ve shown in this study is that these cellular materials can actually move between different cell types by riding in the membrane of exosomes.
“What is so exciting about this discovery is that these exosomes can deliver materials from one cell, over a distance, to a very specific and different cell,” said Dr. Budnik. “Once inside the recipient cell, the materials contained in the exosome can influence or perform processes in the new cell. This raises the enticing possibility that exosomes can be packed with gene therapies, such as RNAi, and delivered to diseased cells where they could have a therapeutic effect for people.”
Discovered in the mid-80s, exosomes have only recently attracted the attention of scientists at large, according to Budnik. Exosomes are small vesicles containing cellular materials such as microRNA, messenger RNAs (mRNAs) and proteins, packaged inside larger, membrane-bound bodies called multivesicular bodies (MVBs) inside cells. When MVBs containing exosomes fuse with the cell plasma membrane, they release these exosome vesicles into the extracellular space. Once outside the cell, exosomes can then travel to other cells, where they are taken up. The recipient cells can then use the materials contained within exosomes, influencing cellular function and allowing the recipient cell to carry out certain processes that it might not be able to complete otherwise.
Budnik and colleagues made this startling discovery while investigating how the synapses at the end of neurons and nearby muscle cells communicate in the developing Drosophila fruit fly to form the neuromuscular junction (NMJ). The NMJ is essential for transmitting electrical signals between neurons and muscles, allowing the organism to move and control important physiological processes. Alterations of the NMJ can lead to devastating diseases, such as muscular dystrophy and Amyotrophic lateral sclerosis (ALS). Understanding how the NMJ develops and is maintained is important for human health.
As organisms develop, the synapse and muscle cell need to grow in concert. If one or the other grows too quickly or not quickly enough, it could have dire consequences for the ability of the organism to move and survive. To coordinate development, signals are sent from the neuron to the muscle cell (anterograde signals) and from the muscle cell to the neuron (retrograde signals). However, the identity of these signals and how their release is coordinated is poorly understood.
Normally, the vesicle protein Synaptotagmin 4 (Syt4) is found in both the synapse and the muscle cells. Previous knockout experiments eliminating the Syt4 protein from Drosophila have resulted in stunted NMJs. Suspecting that Syt4 played an important role in retrograde signaling at the developing NMJ, Budnik and colleagues used knockdown experiments to decrease Syt4 protein levels in either the neurons or the muscle cells. Surprisingly, when RNAi was used to knockdown Syt4 in the neurons alone, Syt4 protein was eliminated in both neurons and muscles. The opposite was not the case. When Syt4 was knocked down in muscle cells only, there was no change in the levels of Syt4 in either muscles or neurons.
To confirm this, Budnik and colleagues inserted a Syt4 gene into the neurons of a Drosophila mutant completely lacking the normal protein. This restored Syt4 in both neurons and muscle cells. Further experiments suggested that the only source of Syt4 is the neuron. These observations were consistent with the model that Syt4 is actually transferred from neurons to muscle cells. As a transmembrane protein, however, Syt4 was thought to be unable to move from one cell to another through traditional avenues. How the Syt4 protein was moving from neuron to muscle cell was unclear.
Knowing that exosomes had been observed to carry transmembrane proteins in other systems and from their own work on the Drosophila NMJ, Budnik and colleagues began testing to see if exosomes could be the vehicle responsible for carrying Syt4 form neurons to muscles. “We had previously observed that it was possible to transfer transmembrane proteins across the NMJ through exosomes, a process also observed in the immune system,” said Budnik. “We suspect this was how Syt4 was making its way from the neuron to the muscle.”
When exosomes were purified from cultured cells containing Syt4, they found that exosomes indeed contained Syt4. In addition, when these purified exosomes were applied to cultured muscle cells from fly embryos, these cells were able to take up the purified Syt4 exosomes. Taken together, these findings indicate that Syt4 plays a critical role in the signaling process between synapse and muscle cell that allows for coordinated development of the NMJ. While Syt4 is required to release a retrograde signal from muscle to neuron, a component of this retrograde signal must be supplied from the neuron to the muscle. This establishes a positive feedback loop that ensures coordinated growth of the NMJ. Equally important is the finding that this feedback mechanism is enabled by the use of exosomes, which can shuttle transmembrane proteins across cells.
“While this discovery greatly enhances our understanding of how the neural muscular junction develops and works, it also has tremendous promise as a potential vector for targeted genetic therapies,” said Budnik. “More work needs to be done, but this study significantly supports the possibility that exosomes could be loaded with therapeutic agents and delivered to specific cells in patients.”
(Source: umassmed.edu)
Nerve regeneration research and therapy may get boost from new discovery
A new mechanism for guiding the growth of nerves that involves cell-death machinery has been found by scientists at the University of Nevada, Reno that may bring advances in neurological medicine and research. The team obtained the evidence in studies of fruit flies and reported their discovery in an article published in the prestigious science publication Cell Reports.
"Although the fly is a relatively simple organism, almost every gene identified in this species appears to be carrying out similar functions in humans," said Thomas Kidd, associate professor in the University’s biology department in whose lab the work was performed.
The Kidd lab is part of a $10 million Center for Biomedical Research Excellence Project in Cell Biology of Signaling at the University, which is funded by the National Institute of Health’s Institute of General Medical Sciences. The project is also funded by the National Science Foundation.
"Flies are useful because the neural mechanisms we are studying are similar to those in mammals," said Gunnar Newquist, lead author of the Cell Reports article and a post-doctoral neuroscience researcher in Kidd’s lab. "We’ve found something no one has seen before, that blocking the cell-death pathway can make nerves deprived of guidance cues figure out the right way to connect with other neurons. This was completely unexpected and novel, but really exciting because it changes the way we look at nerve growth.
"Neurons have a natural ability to die, if they fail to make the right connections they usually die. Neurons, like most other cell types, have the capacity to commit suicide and many do so during the formation of the nervous system."
The wiring of nervous systems is composed of axons, specialized extensions of neurons that transmit electrical impulses. During development axons navigate long distances to their targets by using signals in their environment. Netrin-B is one of those signals. Kidd, Newquist and colleagues have shown that Netrin-B also keeps neurons alive.
"Take away the Netrin-B and growth and cell death goes haywire," Newquist said.
This led them to the discovery that the cell-death machinery is active in growing nerves, and appears to be an integral part of the navigation mechanism.
"We use fruit fly genetics to study how these axons navigate these long distances correctly when developing," Kidd said. "Understanding the mechanisms they use to navigate is of great interest, not only for understanding how our brains form, but also as a starting point to devise ways to stimulate the re-growth of axons after injury, especially spinal cord injuries.
"Our work suggests that therapeutics designed to keep neurons alive after injury may be able to stimulate neurons to start re-growing or sprouting new connections."
"I am very pleased to see Tom’s and Gunnar’s hard work come to fruition," said Chris von Bartheld, director of the University’s cell-biology COBRE and a professor in the University of Nevada School of Medicine. "Linking axonal path finding and cell death signaling opens exciting new venues to better understand both topics. It also shows that our recently established center in cell biology is achieving its goals of producing top-level biomedical research."
(Source: unr.edu)
Hunger-spiking neurons could help control autoimmune diseases
Neurons that control hunger in the central nervous system also regulate immune cell functions, implicating eating behavior as a defense against infections and autoimmune disease development, Yale School of Medicine researchers have found in a new study published in the Proceedings of the National Academies of Sciences (PNAS).
Autoimmune diseases have been on a steady rise in the United States. These illnesses develop when the body’s immune system turns on itself and begins attacking its own tissues. The interactions between different kinds of T cells are at the heart of fighting infections, but they have also been linked to autoimmune disorders.
“We’ve found that if appetite-promoting AgRP neurons are chronically suppressed, leading to decreased appetite and a leaner body weight, T cells are more likely to promote inflammation-like processes enabling autoimmune responses that could lead to diseases like multiple sclerosis,” said lead author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.
“If we can control this mechanism by adjusting eating behavior and the kinds of food consumed, it could lead to new avenues for treating autoimmune diseases,” he added.
Horvath and his research team conducted their study in two sets of transgenic mice. In one set, they knocked out Sirt1, a signaling molecule that controls the hunger-promoting neuron AgRP in the hypothalamus. These Sirt1-deficient mice had decreased regulatory T cell function and enhanced effector T cell activity, leading to their increased vulnerability in an animal model of multiple sclerosis.
“This study highlights the important regulatory role of the neurons that control appetite in peripheral immune functions,” said Horvath. “AgRP neurons represent an important site of action for the body’s immune responses.”
The team’s data support the idea that achieving weight loss through the use of drugs that promote a feeling of fullness “could have unwanted effects on the spread of autoimmune disorders,” he notes.