Posts tagged nerve cells
Articles and news from the latest research reports.
Critical Gene in Retinal Development and Motion Sensing Identified
Our vision depends on exquisitely organized layers of cells within the eye’s retina, each with a distinct role in perception. Johns Hopkins researchers say they have taken an important step toward understanding how those cells are organized to produce what the brain “sees.” Specifically, they report identification of a gene that guides the separation of two types of motion-sensing cells, offering insight into how cellular layering develops in the retina, with possible implications for the brain’s cerebral cortex. A report on the discovery is published in the Nov. 1 issue of the journal Science.
“The separation of different types of cells into layers is critical to their ability to form the precise sets of connections with each other — the circuitry — that lets us process visual information,” says Alex Kolodkin, Ph.D., a professor in the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience and an investigator at the Howard Hughes Medical Institute. “There is still much to learn about how that separation happens during development, but we’ve identified for the first time proteins that enable two very similar types of cells to segregate into their own distinct neuronal layers.”
Kolodkin’s research group specializes in studying how circuitry forms among neurons (brain and nerve cells). Past experiments revealed that two types of proteins, called semaphorins and plexins, help guide this process. In the current study, Lu Sun, a graduate student in Kolodkin’s laboratory, focused on the genes that carry the blueprint for these proteins in two of the 10 layers of cells in the mammalian retina.
Those two layers are made up of so-called starburst amacrine cells (SACs). One type of SAC, known as “Off,” detects motion by sensing decreases in the amount of light hitting the retina, while the other type, “On,” detects increases in light. Sun examined the amounts of several semaphorin and plexin proteins being made by each type of cell, and found that only the “On” SACs were making a semaphorin called Sema6A. Sema6A can only work in the retina by interacting with its receptor, a plexin called PlexA2, but Sun found both types of SAC were churning out roughly equal amounts of PlexA2.
Reasoning that Sema6A might be the key difference that enabled the “On” and “Off” SACs to segregate from one another, Kolodkin’s team analyzed mice in which the genes for either Sema6A, PlexA2 or both could be switched off, and looked at the effects of this manipulation on their retinas. “Knocking out” either gene during development led the “On” and “Off” layers to run together, the team found, and caused abnormalities in the “On” SACs’ tree-like extensions. However, the “Off” SACs, which hadn’t been using their Sema6A gene in the first place, still looked and functioned normally.
“When signaling between Sema6A and PlexA2 was lost, not only was layering compromised, but the ‘On’ SACs lost both their distinctive symmetrical appearance, and, importantly, their motion-detecting ability,” Sun says. “This is evidence that the beautiful symmetric shape that gives starburst amacrine cells their name is necessary for their function.”
Adds Kolodkin, “We hope that learning how layering occurs in these very specific cell types will help us begin sorting out how connections are made not just in the retina, but also in neurons throughout the nervous system. Layering also occurs in the cerebral cortex, for example, which is responsible for thought and consciousness, and we really want to know how this is organized during neural development.”
(Source: newswise.com)
The pig, the fish and the jellyfish: Tracing nervous disorders in humans
What do pigs, jellyfish and zebrafish have in common? It might be hard to discern the connection, but the different species are all pieces in a puzzle. A puzzle which is itself part of a larger picture of solving the riddles of diseases in humans.
The pig, the jellyfish and the zebrafish are being used by scientists at Aarhus University to, among other things, gain a greater understanding of hereditary forms of diseases affecting the nervous system. This can be disorders like Parkinson’s disease, Alzheimer’s disease, autism, epilepsy and the motor neurone disease ALS.
In a project, which has just finished, the scientists have focussed on a specific gene in pigs. The gene, SYN1, encodes the protein synapsin, which is involved in communication between nerve cells. Synapsin almost exclusively occurs in nerve cells in the brain. Parts of the gene can thus be used to control an expression of genes connected to hereditary versions of the aforementioned disorders.
The pig
The SYN1 gene can, with its specific expression in nerve cells, be used for generation of pig models of neurodegenerative diseases like Parkinson’s. The reason scientists bring a pig into the equation is that the pig is well suited as a model for investigating human diseases.
- Pigs are very like humans in their size, genetics, anatomy and physiology. There are plenty of them, so they are easily obtainable for research purposes, and it is ethically easier to use them than, for example, apes, says senior scientist Knud Larsen from Aarhus University.
Before the gene was transferred from humans to pigs, the scientists had to ensure that the SYN1 gene was only expressed in nerve cells. This was where the zebra fish entered the equation.
The zebrafish and the jellyfish
- The zebrafish is, as a model organism, the darling of researchers, because it is transparent and easy to genetically modify. We thus attached the relevant gene, SYN1, to a gene from a jellyfish (GFP), and put it into a zebrafish in order to test the specificity of the gene, explains Knud Larsen.
This is because jellyfish contain a gene that enables them to light up. This gene was transferred to the zebrafish alongside SYN1, so that the scientists could follow where in the fish activity occurred as a result of the SYN1 gene.
- We could clearly see that the transparent zebrafish shone green in its nervous system as a result of the SYN1 gene from humans initiating processes in the nervous system. We could thus conclude that SYN1 works specifically in nerve cells, says Knud Larsen.
The results of this investigation pave the way for the SYN1 gene being used in pig models for research into human diseases. The pig with the human gene SYN1 can presumably also be used for research into the development of the brain and nervous system in the foetus.
- I think it is interesting that the nervous system is so well preserved, from an evolutionary point of view, that you can observe a nerve-cell-specific expression of a pig gene in a zebrafish. It is impressive that something that works in a pig also works in a fish, says Knud Larsen.
Read the scientific article here.
Pulse propagation and signal transduction in the hydraulic brain
When Descartes turned his critical eye to the nervous system, he reasoned that the nerves must transduce hydraulic power to control the musculature. In the circulatory system, blood is pushed comparatively slowly through the aorta, perhaps around 0.3 meters per second. Superimposed on that flow, however, is an arterial pulse wave which propagates much faster, both through the blood and the walls of the vessel. For compliant and healthy vessels that speed might be around 10 meters per second, while for more hardened arteries, it could be 15 or higher. Modern day electrophysiologists have since replaced the hydraulic model with the idea that nerves really only transmit information—electrical information no less. Yet when looking at the power supply to the leg, for example, it is still hard to ignore the fact that the main femoral artery, at a diameter scarcely a half of an inch, looks rather meager next to the “information-supplying” sciatic nerve, which may actually be more like three-quarters of an inch. A conflux of ideas from a variety of disciplines has recently led to a critical re-emergence of the more mechanical side of the nervous system. To that point, two German scientists have just published a paper in the journal, Medical Hypotheses, where they suggest that the pulse wave is the main event in nervous conduction, while the electrical show is mere epiphenomenon.
We recently discussed the increasingly popular idea that action potentials may actually be soliton waves which propagate in the membranes of axons as phase transitions with minimal loss in energy. Convincing biologists that these subtle creatures could exist in the chaotic and varied conditions inside neurons has been a challenge. However, it is harder to argue against the fact that any kind of electrochemical spike based on the rapid influx of ions will be accompanied by a significant pressure pulse. The idea that the German researchers have supported, is that these as the pressure pulses naturally decay in the viscoelastic medium of the nerve, they are refreshed by ionic input at the nodes between myelinated axon segments, or continuously in unmyelinated axons.
If you have ever been absent-minded enough to grab a live wire, or even brush up strongly against one, the sensation is unforgettable. It is not such a stretch to acknowledge that when you slam your funny bone, or more precisely the Ulnar nerve (largest unprotected nerve in your body), the resultant vibe and decay feels almost identical to a real electrical assault. Similarly, the so-called “stingers” that run down the limbs after a sharp blow to the head are familiar to most footballers, and can give one quite a shock. Unfortunately these (albeit very simplistic) macroscopic intuitions don’t hold up so well when extended to the microscopic domain. Granted, when the electrochemical mechanisms that are assumed to underlie nervous conduction are looked at in detail, it becomes more difficult to disentangle the mechanical from the electric. However, as the authors observe, at some point, an attentive electrophysiologist must ask his or herself, “why are so many ion channels mechanosensitive” ?
One unexpected finding of the patch clamp recording technique was that the dilation of the membrane caused by local tension leads to considerable increase in transmembrane ion flow. Impulse waves causing short extensions in the membrane can directly induce opening and closing of both voltage and ligand gated channels. The idea that the pore in these channels is a rigid tube isolated from larger membrane events is difficult to support in this context. According to the authors, it is quite likely that common mechanoreceptor devices, like the pressure- or vibration-sensitive Vater-Pacinian corpuscles of the skin, conduct signals to initiate high-speed polysynaptic muscle reflex circuits without any classical intermediary electrical conversion.
The exact conduction velocity of mechanical impulses in nerve fibers remains unknown. It is estimated that under physiologic conditions, an unamplified axoplasmic pressure pulse would decay over roughly 1 mm due to viscosity, depending on the distensibility of the axon wall. When compared to the theoretical case of an absolutely rigid wall, a typical myelin sheath may be rigid enough to support pulse speeds up to one-fifth of the estimated maximum. That speed is not to shabby when compared with some rough estimates from previous authors, which put the maximum pulse velocity under an indistensible membrane somewhere upwards of 1500 meters per second. Suddenly, the quicker than life eyeblink response, or speed of the tenderfoot stepping on a sharp shard, become a little more comprehensible.
The theory as it stands is incomplete and needs to be adapted for specific cases with real biology in mind. In different animals, and in different regions of their brains, conduction in neurons goes by different names. For example, in the cerebellum, the unmyelinated parallel fibers pack to extreme densities in a regular crystalline lattice whose reason to be defies physiologic explanation to this day. Just as we currently have no good explanation for how signals could be properly isolated in nerve bundles where seemingly random nodes of Ranvier overlap in extent and influence, it is hard to imagine parallel fibers could maintain their electrochemical, or even mechanical, autonomy within this geometry.
The pressure wave theory wields considerable predictive power when it comes to explaining some of the unique synaptic specializations found throughout the brain. When considered only from an electrochemical point of view, the huge structural synaptic investments, like those found at the neuromuscular junction (NMJ), can hardly be imagined to be driven by local, and weak, current or field effects. One might need look no further than simple-to-recreate Chaldni patterns set up in two dimensions on the surface of a taunt drum, to make the imaginative leap to a three dimensional system, with multiple vibrating players, where more extreme patterns might easily be set up to provide authorship to repeatable complex structure. For the NMJ in particular, the case has been made that at the end-plate, the comparatively enormous efflux of acetylcholine to the deeply-guttered cleft, and propagation of excitation through the transverse tubule system, are all components of a continuous mechanical amplifier.
The apparent ease with which evolving organisms manage to cobble together all manner of sensitive hearing devices becomes infinitely more explicable once we see that nature has apparently been doing this kind of thing all alone inside of neurons. The amplification and transduction through liquid channels, of barely noticeable vibrations against a background of thermal noise much greater in magnitude, is in this light, no evolutionary stumble-upon, but rather the bread and butter of neural systems, and perhaps many aspects of life in general.
Researchers Pinpoint Molecular Path that Makes Antidepressants Act Quicker in Mouse Model
Understanding alternate pathways for how mental meds work could lead to faster-acting drug targets
The reasons behind why it often takes people several weeks to feel the effect of newly prescribed antidepressants remains somewhat of a mystery – and likely, a frustration to both patients and physicians.
(Image: Mouse hippocampus expressing the Cre- virus. Credit: Julie Blendy, PhD; Brigitta Gunderson, PhD; Perelman School of Medicine, University of Pennsylvania)
Julie Blendy, PhD, professor of Pharmacology, at the Perelman School of Medicine, University of Pennsylvania; Brigitta Gunderson, PhD, a former postdoctoral fellow in the Blendy lab, and colleagues, have been working to find out why and if there is anything that can be done to shorten the time in which antidepressants kick in.
“Our goal is to find ways for antidepressants to work faster,” says Blendy.
The proteins CREB and CREM are both transcription factors, which bind to specific DNA sequences to control the “reading” of genetic information from DNA to messenger RNA (mRNA). Both CREB and CREM bind to the same 8-base-pair DNA sequence in the cell nucleus. But, the comparative influence of CREM versus CREB on the action of antidepressants is a “big unknown,” says Blendy.
CREB, and CREM to some degree, has been implicated in the pathophysiology of depression, as well as in the efficacy of antidepressants. However, whenever CREB is deleted, CREM is upregulated, further complicating the story.
Therefore, how an antidepressant works on the biochemistry and behavior in a mouse in which the CREB protein is deleted only in the hippocampus versus a wild type mouse in which CREM is overexpressed let the researchers tease out the relative influence of CREB and CREM on the pharmacology of an antidepressant. They saw the same results in each type of mouse line – increased nerve-cell generation in the hippocampus and a quicker response to the antidepressant. Their findings appear in the Journal of Neuroscience.
“This is the first demonstration of CREM within the brain playing a role in behavior, and specifically in behavioral outcomes, following antidepressant treatment,” says Blendy.
A Flood of Neurotransmitters
Antidepressants like SSRIs, NRIs, and older tricyclic drugs work by causing an immediate flood of neurotransmitters like serotonin, norepinephrine, and in some cases dopamine, into the synaptic space. However, it can take three to four weeks for patients to feel changes in mental state. Long-term behavioral effects of the drugs may take longer to manifest themselves, because of the need to activate CREB downstream targets such as BDNF and trkB, or as of yet unidentified targets, which could also be developed as new antidepressant drug targets.
The Penn team compared the behavior of the control, wild-type mice to the CREB mutant mice using a test in which the mouse is trained to eat a treat – Reese’s Pieces, to be exact – in the comfort of their home cage. The treat-loving mice are then placed in a new cage to make them anxious. They are given the treat again, and the time it takes for the mouse to approach the treat is recorded.
Animals that receive no drug treatment take a long time to venture out into the anxious environment to retrieve the treat, however, if given an antidepressant drug for at least three weeks, the time it takes a mouse to get the treat decreases significantly, from about 400 seconds to 100 seconds. In mice in which CREB is deleted or in mice in which CREM is upregulated, this reduction happens in one to two days versus the three weeks seen in wild-type mice.
The accelerated time to approach the treat in mice on the medication was accompanied by an increase in new nerve growth in the hippocampus.
“Our results suggest that activation of CREM may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment,” says Blendy. Upregulation of CREM observed after CREB deletion, appears to functionally compensate for CREB loss at a behavioral level and leads to maintained or increased expression of some CREB target genes. The researchers’ next step is to identify any unique CREM target genes in brain areas such as the hippocampus, which may lead to the development of faster-acting antidepressants.
(Source: uphs.upenn.edu)
Capturing brain activity with sculpted light
Researchers in Vienna develop new imaging technique to study the function of entire nervous systems. Scientists at the Campus Vienna Biocenter (Austria) have found a way to overcome some of the limitations of light microscopy. Applying the new technique, they can record the activity of a worm’s brain with high temporal and spatial resolution, ultimately linking brain anatomy to brain function. The journal Nature Methods publishes the details in its current issue.
A major aim of today’s neuroscience is to understand how an organism’s nervous system processes sensory input and generates behavior. To achieve this goal, scientists must obtain detailed maps of how the nerve cells are wired up in the brain, as well as information on how these networks interact in real time.
The organism many neuroscientists turn to in order to study brain function is a tiny, transparent worm found in rotting soil. The simple nematode C. elegans is equipped with just 302 neurons that are connected by roughly 8000 synapses. It is the only animal for which a complete nervous system has been anatomically mapped.
Researchers have so far focused on studying the activity of single neurons and small networks in the worm, but have not been able to establish a functional map of the entire nervous system. This is mainly due to limitations in the imaging-techniques they employ: the activity of single cells can be resolved with high precision, but simultaneously looking at the function of all neurons that comprise entire brains has been a major challenge. Thus, there was always a trade-off between spatial or temporal accuracy and the size of brain regions that could be studied.
Scientists at Vienna’s Research Institute of Molecular Pathology (IMP), the Max Perutz Laboratories (MFPL), and the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna have now closed this gap and developed a high speed imaging technique with single neuron resolution that bypasses these limitations. In a paper published online in Nature Methods, the teams of Alipasha Vaziri and Manuel Zimmer describe the technique which is based on their ability to “sculpt” the three-dimensional distribution of light in the sample. With this new kind of microscopy, they are able to record the activity of 70% of the nerve cells in a worm’s head with high spatial and temporal resolution.
“Previously, we would have to scan the focused light by the microscope in all three dimensions”, says quantum physicist Robert Prevedel. “That takes far too long to record the activity of all neurons at the same time. The trick we invented tinkers with the light waves in a way that allows us to generate “discs” of light in the sample. Therefore, we only have to scan in one dimension to get the information we need. We end up with three-dimensional videos that show the simultaneous activities of a large number of neurons and how they change over time.” Robert Prevedel is a Senior Postdoc in the lab of Alipasha Vaziri, who is an IMP-MFPL Group Leader and is heading the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna, where the new technique was developed.
However, the new microscopic method is only half the story. Visualising the neurons requires tagging them with a fluorescent protein that lights up when it binds to calcium, signaling the nerve cells’ activity. “The neurons in a worm’s head are so densely packed that we could not distinguish them on our first images”, explains neurobiologist Tina Schrödel, co-first author of the study. “Our solution was to insert the calcium sensor into the nuclei rather than the entire cells, thereby sharpening the image so we could identify single neurons.” Tina Schrödel is a Doctoral Student in the lab of the IMP Group Leader Manuel Zimmer.
The new technique that came about by a close collaboration of physicists and neurobiologists has great potentials beyond studies in worms, according to the researchers. It will open up the way for experiments that were not possible before. One of the questions that will be addressed is how the brain processes sensory information to “plan” specific movements and then executes them. This ambitious project will require further refinement of both the microscopy methods and computational methods in order to study freely moving animals. The team in Vienna is set to achieve this goal in the coming two years.
Shout now! ‒ How Nerve Cells Initiate Voluntary Calls
University of Tübingen neuroscientists show that monkeys can decide to call out or keep silent
“Should I say something or not?” Human beings are not alone in pondering this dilemma – animals also face decisions when they communicate by voice. University of Tübingen neurobiologists Dr. Steffen Hage and Professor Andreas Nieder have now demonstrated that nerve cells in the brain signal the targeted initiation of calls – forming the basis of voluntary vocal expression. Their results are published in “Nature Communications.”
When we speak, we use the sounds we make for a specific purpose – we intentionally say what we think, or consciously withhold information. Animals, however, usually make sounds according to what they feel at that moment. Even our closest relations among the primates make sounds as a reflex based on their mood. Now, Tübingen neuroscientists have shown that rhesus monkeys are able to call (or be silent) on command. They can instrumentalize the sounds they make in a targeted way, an important behavioral ability which we also use to put language to a purpose.
To find out how the neural cells in the brain catalyse the production of controled vocal noises, the researchers taught rhesus monkeys to call out quickly when a spot appeared on a computer screen. While the monkeys solved puzzles, measurements taken in their prefrontal cortex revealed astonishing reactions in the cells there. The nerve cells became active whenever the monkey saw the spot of light which was the instruction to call out. But if the monkey simply called out spontaneously, these nerve cells were not activated. The cells therefore did not signaled for just any vocalisation – only for calls that the monkey actively decided to make.
The results published in “Nature Communications” provide valuable insights into the neurobiological foundations of vocalization. “We want to understand the physiological mechanisms in the brain which lead to the voluntary production of calls,” says Dr. Steffen Hage of the Institute for Neurobiology, “because it played a key role in the evolution of human ability to use speech.” The study offers important indicators of the function of part of the brain which in humans has developed into one of the central locations for controlling speech. “Disorders in this part of the human brain lead to severe speech disorders or even complete loss of speech in the patient,” Professor Andreas Nieder explains. The results – giving insights into how the production of sound is initiated – may help us better understand speech disorders.
(Source: uni-tuebingen.de)
Biologists Uncover Details of How We Squelch Defective Neurons
Biologists at the University of California, San Diego have identified a new component of the cellular mechanism by which humans and animals automatically check the quality of their nerve cells to assure they’re working properly during development.
In a paper published in this week’s issue of the journal Neuron, the scientists report the discovery in the laboratory roundworm C. elegans of a “quality check” system for neurons that uses two proteins to squelch the signals from defective neurons and marks them for either repair or destruction.
“To be able to see, talk and walk, nerve cells in our body need to communicate with their right partner cells,” explains Zhiping Wang, the lead author in the team of researchers headed by Yishi Jin, a professor of neurobiology in UC San Diego’s Division of Biological Sciences and a professor of cellular and molecular medicine in its School of Medicine. “The communication is mediated by long fibers emitting from neurons called axons, which transmit electric and chemical signals from one cell to the other, just like cables connecting computers in a local wired network. In developing neurons, the journey of axons to their target cells is guided by a set of signals. These signals are detected by ‘mini-receivers’—proteins called guidance receptors—on axons and translated into ‘proceed,’ ‘stop,’ ‘turn left’ or ‘turn right.’ Thus, the quality of these receivers is very important for the axons to interpret the guiding signals.”
Jin, who is also an Investigator of the Howard Hughes Medical Institute, says defective protein products and environmental stress, such as hyperthermia, can sometimes jeopardize the health and development of cells. “This may be one reason why pregnant women are advised by doctors to avoid saunas and hot tubs,” she adds.
The scientists discovered the quality check system in roundworms, and presumably other animals including humans, consists of two parts: a protein-cleaning machine containing a protein called EBAX-1, and a well-known protein assembly helper called heat-shock protein 90 known as “hsp90.”
“Hsp90 facilitates the assembly of guidance receivers during the production and also fixes flawed products whenever they are detected,” says Andrew Chisholm, a professor of neurobiology and cell and developmental biology, who also helped lead the study. “The EBAX-containing protein-cleaning machine is in charge of destroying any irreparable products so that they don’t hang around and affect the performance of functional receivers. The EBAX-1 protein plays as a defectiveness detector in this machine and a connector to Hsp90. It captures defective products and presents them for either repair or destruction.”
A human neurodevelopmental disorder called “horizontal gaze palsy with progressive scoliosis” is associated with the defective production of one of the protein guidance receivers. This team of researchers showed that the defective human protein can interact with EBAX proteins. The authors hope that by investigating the action of EBAX-1 protein, their findings will provide clues to develop remedies or drugs to retreat human disorders in the future.
Sleep Boosts Production of Brain Support Cells
Animal study shows genes involved in brain repair, growth turned on during slumber
Sleep increases the reproduction of the cells that go on to form the insulating material on nerve cell projections in the brain and spinal cord known as myelin, according to an animal study published in the September 4 issue of The Journal of Neuroscience. The findings could one day lead scientists to new insights about sleep’s role in brain repair and growth.
Scientists have known for years that many genes are turned on during sleep and off during periods of wakefulness. However, it was unclear how sleep affects specific cells types, such as oligodendrocytes, which make myelin in the healthy brain and in response to injury. Much like the insulation around an electrical wire, myelin allows electrical impulses to move rapidly from one cell to the next.
In the current study, Chiara Cirelli, MD, PhD, and colleagues at the University of Wisconsin, Madison, measured gene activity in oligodendrocytes from mice that slept or were forced to stay awake. The group found that genes promoting myelin formation were turned on during sleep. In contrast, the genes implicated in cell death and the cellular stress response were turned on when the animals stayed awake.
“These findings hint at how sleep or lack of sleep might repair or damage the brain,” said Mehdi Tafti, PhD, who studies sleep at the University of Lausanne in Switzerland and was not involved with this study.
Additional analysis revealed that the reproduction of oligodendrocyte precursor cells (OPCs) — cells that become oligodendrocytes — doubles during sleep, particularly during rapid eye movement (REM), which is associated with dreaming.
“For a long time, sleep researchers focused on how the activity of nerve cells differs when animals are awake versus when they are asleep,” Cirelli said. “Now it is clear that the way other supporting cells in the nervous system operate also changes significantly depending on whether the animal is asleep or awake.”
Additionally, Cirelli speculated the findings suggest that extreme and/or chronic sleep loss could possibly aggravate some symptoms of multiple sclerosis (MS), a disease that damages myelin. Cirelli noted that future experiments may examine whether or not an association between sleep patterns and severity of MS symptoms exists.
The white arrow highlights the primary neuronal cilium, a hair-like structure on nerve cells. The neuron on the right has no cilium because of the loss of a protein linked to intellectual disability in humans. Credit: YOSHIHO IKEUCHI
Intellectual disability linked to nerve cells that lose their ‘antennae’
An odd and little-known feature of nerve cells may be linked to several forms of inherited intellectual disability, researchers at Washington University School of Medicine in St. Louis have learned.
The scientists report that a genetic mutation that causes intellectual disability also blocks formation of the neuronal primary cilium, a hair-like structure that protrudes from the bodies of nerve cells.
"The primary cilium acts as a kind of antenna for nerve cells,” said first author Yoshiho Ikeuchi, PhD, a staff scientist. “It’s covered in receptors that monitor environmental conditions outside the cell and may influence the cell’s functions.”
Learning more about how the mutation sabotages production of the nerve cell cilium eventually will help scientists develop drugs to treat intellectual disability, according to senior author Azad Bonni, MD, PhD, the Edison Professor and chairman of the Department of Anatomy and Neurobiology.
"Intellectual disability—sometimes known as mental retardation—affects 1 to 2 percent of the general population, and researchers have identified more than 100 genes on the X chromosome that can cause these conditions,” Bonni said. “But we don’t know what most of these genes do, and that information is essential for new treatments.”
The research appears online Aug. 29 in Cell Reports.
Nearly every cell in the mammalian body has a primary cilium—a structure that acts as an environmental sensor. Some cells have many cilia that move together in waves. Problems with cilia are associated with disorders throughout the body, including illnesses of the kidneys, eyes and reproductive organs.
"Some of the X-linked intellectual disorders are syndromes that not only hamper brain development but also cause problems elsewhere in the body,” Bonni said. “That makes sense in the context of this new connection we’ve identified between intellectual disability and the primary cilium.”
Scientists only recently have recognized the potential of a primary cilium malfunction to impair nerve cell development and function. Studies have suggested that the primary cilium may be where nerve cells receive the growth signals that allow them to extend branches to each other and form circuits. Other research has shown that blocking of signal receptors on the primary cilium leads to memory problems in mice.
Bonni’s path to the primary cilium led through the nucleus, the command center that contains a cell’s DNA. Proteins found inside a cell’s nucleus often regulate the turning on or off of other genes, making them influential in orchestrating the responses and functions of cells.
Bonni and his colleagues scanned the literature on X chromosome genes linked to intellectual disability to learn which genes produce proteins found in the nucleus. When they disabled 15 such genes in individual nerve cells, they found that the loss of the gene for polyglutamine-binding protein 1 (PQBP1) produced the most dramatic effect, leaving nerve cells with shortened primary cilia or no cilia at all.
In other cell types outside the brain, PQBP1 is typically found only in the nucleus. But the new results show that in neurons the protein is present both in the nucleus and, surprisingly, at the base of the primary cilium.
The scientists learned PQBP1 binds to another protein outside the nucleus that suppresses growth of the primary cilium. By binding to the suppressor, PQBP1 gets that suppressor out of the way, allowing cilium formation to proceed normally.
Scientists may one day try to imitate this effect with drugs, potentially allowing the brain to develop more normally when PQBP1 is mutated. For now, the researchers want to learn more about the suppressor protein and also are investigating the possibility that PQBP1 may continue to influence the functions of the primary cilium after it is formed.
Receptor may aid spread of Alzheimer’s and Parkinson’s in brain
Scientists at Washington University School of Medicine in St. Louis have found a way that corrupted, disease-causing proteins spread in the brain, potentially contributing to Alzheimer’s disease, Parkinson’s disease and other brain-damaging disorders.
Image: An electron micrograph shows clumps of corrupted tau protein outside a nerve cell. Scientists have identified a receptor that lets these clumps into the cell, where the corruption can spread. Blocking this receptor with drugs may help treat Alzheimer’s, Parkinson’s and other disorders.
The research identifies a specific type of receptor and suggests that blocking it may aid treatment of theses illnesses. The receptors are called heparan sulfate proteoglycans (HSPGs).
“Many of the enzymes that create HSPGs or otherwise help them function are good targets for drug treatments,” said senior author Marc I. Diamond, MD, the David Clayson Professor of Neurology. “We ultimately should be able to hit these enzymes with drugs and potentially disrupt several neurodegenerative conditions.”
The study is available online in the Proceedings of the National Academy of Sciences.
Over the last decade, Diamond has gathered evidence that Alzheimer’s disease and other neurodegenerative diseases spread through the brain in a fashion similar to conditions such as mad cow disease, which are caused by misfolded proteins known as prions.
Proteins are long chains of amino acids that perform many basic biological functions. A protein’s abilities are partially determined by the way it folds into a 3-D shape. Prions are proteins that have become folded in a fashion that makes them harmful.
Prions spread across the brain by causing other copies of the same protein to misfold.
Among the most infamous prion diseases are mad cow disease, which rapidly destroys the brain in cows, and a similar, inherited condition in humans called Creutzfeldt-Jakob disease.
Diamond and his colleagues have shown that a part of nerve cells’ inner structure known as tau protein can misfold into a configuration called an amyloid. These corrupted versions of tau stick to each other in clumps within the cells. Like prions, the clumps spread from one cell to another, seeding further spread by causing copies of tau protein in the new cell to become amyloids.
In the new study, first author Brandon Holmes, an MD/PhD student, showed that HSPGs are essential for binding, internalizing and spreading clumps of tau. When he genetically disabled or chemically modified the HSPGs in cell cultures and in a mouse model, clumps of tau could not enter cells, thus inhibiting the spread of misfolded tau from cell to cell.
Holmes also found that HSPGs are essential for the cell-to-cell spread of corrupted forms of alpha-synuclein, a protein linked to Parkinson’s disease.
“This suggests that it may one day be possible to unify our understanding and treatment of two or more broad classes of neurodegenerative disease,” Diamond said.
“We’re now sorting through about 15 genes to determine which are the most essential for HSPGs’ interaction with tau,” Holmes said. “That will tell us which proteins to target with new drug treatments.”
(Source: news.wustl.edu)