Posts tagged astrocytes
Articles and news from the latest research reports.
Overlooked cells hold keys to brain organization and disease
Scientists studying brain diseases may need to look beyond nerve cells and start paying attention to the star-shaped cells known as “astrocytes,” because they play specialized roles in the development and maintenance of nerve circuits and may contribute to a wide range of disorders, according to a new study by UC San Francisco researchers.
In a study published online April 28, 2014 in Nature, the researchers report that malfunctioning astrocytes might contribute to neurodegenerative disorders such as Lou Gehrig’s disease (ALS), and perhaps even to developmental disorders such as autism and schizophrenia.
David Rowitch, MD, PhD, UCSF professor of pediatrics and neurosurgery and a Howard Hughes Medical Institute investigator, led the research.
The researchers discovered in mice that a particular form of astrocyte within the spinal cord secretes a protein needed for survival of the nerve circuitry that controls reflexive movements. This discovery is the first demonstration that different types of astrocytes exist to support development and survival of distinct nerve circuits at specific locations within the central nervous system.
Astrocytes vastly outnumber signal-conducting neurons, and make up the majority of cells in the brain. But where neuroscientists are accustomed to seeing only vanilla when it comes to astrocytes – viewing all of them as similar despite their different locations in brain and spinal cord — they now will have to imagine “31 flavors” or more.
There might even be hundreds of distinctive varieties of astrocytes performing specific functions in different locations, according to Rowitch, chief of neonatology for UCSF Benioff Children’s Hospital San Francisco.
"Our study shows roles for specialized astrocytes that function to support particular kinds of neurons in their neighborhood," Rowitch said.
Led by Rowitch lab postdoctoral fellow Anna Molofsky, MD, PhD, the researchers studied the spinal cord sensory motor circuit, which allows both mice and humans to react without thought – to jerk a limb away from something hot, for instance.
The team discovered that a protein called Sema3a is produced much more abundantly by astrocytes close to motor neurons than by astrocytes from other regions in the spinal cord. They concluded that motor neurons required this source of Sema3a from the local astrocytes, because when Sema3a production was blocked, the motor neurons failed to form normal connections, and half of them died.
Motor neurons also die in ALS, a fatal neurodegenerative disease, and in spinal muscular atrophy, a disease that can affect newborn infants. In other studies, scientists have found that abnormal astrocytes can have toxic effects on motor neurons.
Molofsky is a psychiatrist who studies how astrocytes organize nerve circuits, and how disruptions of these nerve circuits during development or disease may involve abnormal astrocyte function. Disrupted neural circuits are believed to be responsible for certain psychiatric disorders.
"The immediate implications of this study are for diseases of motor neurons, like ALS, but I think our findings might also apply more generally to diseases of neural-circuit formation in the brain such as autism, schizophrenia and epilepsy," Molofsky said. "To achieve a comprehensive understanding of how neural circuits form and are maintained, it seems important that we integrate knowledge of how astrocytes support that process."
Rowitch agrees. “To the extent that psychiatric or neurological disease is localized to a specific part of the brain, we should now be considering the potentially specialized type of astrocytes regulating nerve connections in that region and their contributions to disease,” he said.
(Image: Astrocytes surround neuronal sysnapses and form networks physically coupled by gap-junctions. Credit: Dr. Takahiro Takano)
Eavesdropping on brain cell chatter
Everything we do — all of our movements, thoughts and feelings – are the result of neurons talking with one another, and recent studies have suggested that some of the conversations might not be all that private. Brain cells known as astrocytes may be listening in on, or even participating in, some of those discussions. But a new mouse study suggests that astrocytes might only be tuning in part of the time — specifically, when the neurons get really excited about something. This research, published in Neuron, was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
For a long time, researchers thought that the star-shaped astrocytes (the name comes from the Greek word for star) were simply support cells for the neurons.
It turns out that these cells have a number of important jobs, including providing nutrients and signaling molecules to neurons, regulating blood flow, and removing brain chemicals called neurotransmitters from the synapse. The synapse is the point of information transfer between two neurons. At this connection point, neurotransmitters are released from one neuron to affect the electrical properties of the other. Long arms of astrocytes are located next to synapses, where they can keep tabs on the conversations going on between neurons.
In recent years, it has been shown that astrocytes may also play a role in neuronal communication. When neurons release neurotransmitters, levels of calcium change within astrocytes. Calcium is critical for many processes, including release of molecules from the cell, and activation of a host of proteins within the cell. The role of this astrocytic calcium signaling for brain function remains a mystery.
In this study, Baljit S. Khakh, Ph.D., of the University of California, Los Angeles and his colleagues wanted to know when astrocytes responded to neuron activity with changes in their internal calcium levels. Using calcium indicator dyes, the researchers were able to image, for the first time, changes in calcium levels in the entire astrocyte. Previously, it was only possible to look at certain areas of the cell at one time, which provided an incomplete picture of what was happening.
Dr. Khakh said one of the most important outcomes of this work was in the methods that were used. “What our use of these calcium indicators shows is that we can image calcium throughout the entire astrocyte. This provides a new set of tools for the research community to use and to extend these findings,” he said.
“There has been intense interest in understanding how astrocytes facilitate communication between neurons, but it is only recently that studies with this level of precision have been possible,” said Edmund Talley, Ph.D., program director at NINDS. “Dr. Khakh’s study is an example of an exciting basic, or fundamental, research project that could have an important contribution to the shifting field of astrocyte biology,” he added.
For these experiments, researchers focused on the mossy fiber pathway, which connects two areas of the hippocampus, the structure involved in learning and memory. “This pathway has a unique architecture and although it has been very well studied, the role of astrocytes in this circuit has not been previously explored. This study provides one of the first really detailed understandings of astrocytes within this particular circuit,” said Dr. Khakh.
Dr. Khakh’s team activated neurons (getting them to release neurotransmitter by a variety of techniques) and then looked for a response in the neighboring astrocyte. As calcium levels rose, the astrocyte would light up quickly. They discovered that two neurotransmitters, glutamate and GABA, triggered the astrocytes to release calcium from their internal stores. Importantly, the researchers discovered that calcium levels increased through the entire astrocyte only if there was a large burst of neurotransmitter being released.
“We found that astrocytes in the mossy fiber pathway do not listen to the constant, millisecond by millisecond synaptic chatter that neurons engage in. Instead, they listen when neurons get excessively excited during bursts of activation,” said Dr. Khakh.
These findings suggest that astrocytes in the mossy fiber system may act as a switch that reacts to large amounts of neuronal activity by raising their levels of calcium. These calcium increases occur over multiple seconds, a relatively long time period compared to that seen in neurons. The spatial extent of the astrocyte calcium increases was also relatively large in comparison to the size of the synapse.
“Astrocytes may be sitting there quietly and when there is excessive activation in the neuronal circuit, they immediately respond with an increase in calcium which we could detect. And the next big question becomes, what they do with that calcium?” said Dr. Khakh.
Dr. Khakh’s results in the mossy fiber system differ from those others have described in other brain regions. This raises the intriguing possibility that astrocytes are not all the same and may serve various roles throughout the brain.
“It would be really interesting and important to find that astrocytes function differently in different areas of the brain, in a circuit-specific manner. This study gives a hint that this might be true,” said Dr. Talley.
Huntington’s disease: Study discovers potassium boost improves walking in mouse model
Tweaking a specific cell type’s ability to absorb potassium in the brain improved walking and prolonged survival in a mouse model of Huntington’s disease, reports a UCLA study published March 30 in the online edition of Nature Neuroscience. The discovery could point to new drug targets for treating the devastating disease, which strikes one in every 20,000 Americans.
Huntington’s disease is passed from parent to child through a mutation in the huntingtin gene. By killing brain cells called neurons, the progressive disorder gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. No cure exists, and patients with aggressive cases can die in as little as 10 years.
The laboratories of Baljit Khakh, a professor of physiology and neurobiology, and Michael Sofroniew, a professor of neurobiology, teamed up at the David Geffen School of Medicine at UCLA to unravel the role played in Huntington’s by astrocytes—large, star-shaped cells found in the brain and spinal cord.
Blood-brain barrier repair after stroke may prevent chronic brain deficits
Following ischemic stroke, the integrity of the blood-brain barrier (BBB), which prevents harmful substances such as inflammatory molecules from entering the brain, can be impaired in cerebral areas distant from initial ischemic insult. This disruptive condition, known as diaschisis, can lead to chronic post-stroke deficits, University of South Florida researchers report.
(Image credit: Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier)
In experiments using laboratory rats modeling ischemic stroke, USF investigators studied the consequences of the compromised BBB at the chronic post-stroke stage. Their findings appear in a recent issue of the Journal of Comparative Neurology.
“Following ischemic stroke, the pathological changes in remote areas of the brain likely contribute to chronic deficits,” said neuroscientist and study lead author Svitlana Garbuzova-Davis, PhD, associate professor in the USF Health Department of Neurosurgery and Brain Repair. “These changes are often related to the loss of integrity of the BBB, a condition that should be considered in the development of strategies for treating stroke and its long-term effects.”
Edward Haller of the USF Department of Integrative Biology, the coauthor who performed electron microscopy and contributed to image analysis, emphasized that “major BBB damage was found in endothelial and pericyte cells, leading to capillary leakage in both brain hemispheres.” These findings were essential in demonstrating persistence of microvascular alterations in chronic ischemic stroke.
While acute stroke is life-threatening, the authors point out that survivors often suffer insufficient blood flow to many parts of the brain that can contribute to persistent damage and disability. Their previous investigation of subacute ischemic stroke showed far-reaching microvascular damage even in areas of the brain opposite from the initial stroke injury. While most studies of stroke and the BBB explore the acute phase of stroke and its effect on the blood-brain barrier, the present study revealed the longer-term effects in various parts of the brain.
The pathologic processes of stroke-induced vascular injury tend to occur in a “time-dependent manner,” and can be separated into acute (minutes to hours), subacute (hours to days), and chronic (days to months). BBB incompetence during post-stroke changes is well-documented, with some studies showing the BBB opening can last up to four to five days after stroke. This suggests that harmful substances entering the brain during this prolonged BBB leakage might increase post-ischemic brain injury.
In this study, the researchers used laboratory rats modeling ischemic stroke and observed injury not only in the primary area of the stroke, but also in remote areas, where persistent BBB damage could cause chronic loss of competence.
“Our results showed that the compromised BBB integrity detected in post-ischemic rat cerebral hemisphere capillaries — both ipsilateral and contralateral to initial stroke insult — might indicate chronic diaschisis,” Garbuzova-Davis said. “Widespread microvascular damage caused by endothelial cell impairment could aggravate neuronal deterioration. For this reason, chronic diaschisis poses as a therapeutic target for stroke.”
The primary focus for therapy development could be restoring endothelial and/or astrocytic integrity towards BBB repair, which may be “beneficial for many chronic stroke patients,” senior authors Cesar V. Borlongan and Paul R. Sanberg suggest. The researchers also recommend that cell therapy might be used to replace damaged endothelial cells.
“A combination of cell therapy and the inhibition of inflammatory factors crossing the blood-brain barrier may be a beneficial treatment for stroke,” Garbuzova-Davis said.
(Source: research.usf.edu)
Bioimaging: Visualizing real-time development of capillary networks in adult brains
The advancement of microscopic photoimaging techniques has enabled the visualization of real-time cellular events in living organs. The brain capillary network exhibits a unique feature that forms a blood-brain barrier (BBB), which is an interface of vascular endothelial cells that control the traffic of substances from the bloodstream into the brain. Damage and disruption to the BBB are implicated in contributing to the pathogenesis and progression of neurodegenerative disorders such as Alzheimer’s and epilepsy. However, the cellular interactions present in the BBB are incredibly difficult to study in vivo, so understanding of these mechanisms in living brains is limited.
Now, Kazuto Masamoto and co-workers at the University of Electro-Communications in Tokyo, National Institute of Radiological Sciences, and Keio University School of Medicine, have used 4D live imaging technology to study the effects of hypoxia (a deprivation of oxygen) on the BBB plasticity in live adult mice.
The team focused their attention on how the BBB plastic changes work against hypoxia, looking in particular at the endothelial cells and their communications to the neighboring astrocytes - interactions which take place in controlling the BBB traffic to fulfill neural demands. Using genetically-modified mice with endothelial cells that express green-fluorescent protein, Masamoto and colleagues imaged the real-time changes of BBBs before and during a three-week period of hypoxia in adult mouse cortex.
Their results showed that the capillaries in the BBB, which prior to hypoxia showed no signs of activity, began to sprout new blood vessels which in places formed new networks together. The neighboring astrocytes reacted quickly to wrap the outside of the new vessels, activity which the researchers believe helps stabilize the BBB traffic and integrity.
Further investigations into the molecular mechanisms that control BBB plasticity are expected to lead to advances in treatment of neurodegenerative disorders and cerebral ischemia, and thus provide an effective way for preventing BBB dysfunction in diabetes, hypertension, and aging.
Researchers generate new neurons in brains, spinal cords of living adult mammals
UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.
Although the research indicates it may someday be possible to regenerate neurons from the body’s own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer’s disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.
Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.
Scientists in UT Southwestern’s Department of Molecular Biology first successfully turned astrocytes – the most common non-neuronal brain cells – into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.
“Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons,” said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies.
“Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration,” Dr. Zhang explained. “Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming.”
The scientists’ two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.
In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.
The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.
In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added.
Because tumor growth is a concern when cells are reprogrammed to an earlier stage of development, the researchers followed the mice in the Nature Cell Biology study for nearly a year to look for signs of tumor formation and reported finding none.
(Image: Shutterstock)
New research sheds light on how the body regulates fundamental neuro-hormone
Researchers at the University of Bristol and University College London found that lactate – essentially lactic acid – causes cells in the brain to release more noradrenaline (norepinephrine in US English), a hormone and neurotransmitter which is fundamental for brain function. Without it people can hardly wake up or focus on anything.
Production of lactate can be triggered by muscle use, which reinforces the connection between exercise and positive mental wellbeing.
Lactate was first discovered in sour milk by Swedish chemist, Carl Wilhelm Scheele in 1780. It is produced naturally by the body, for example when muscles are at work. In the brain, it has always been regarded as an energy source which can be delivered to neurones as fuel to keep them working when brain activity increases.
This research, published today [11 February] in Nature Communications, identifies a secondary function for lactate as a signal between brain cells. It implies that there is an as yet unknown receptor for lactate in the brain which must be present on noradrenaline cells to make them sensitive to lactate.
Professor Sergey Kasparov, from Bristol University’s School of Physiology and Pharmacology, said: “Our findings suggest that lactate has more than one incarnation - in addition to its role as an energy source, it is also a signal to neurones to release more noradrenaline.”
Dr Anja Teschemacher, also from the University of Bristol, added: “The next big task is to identify the receptor which mediates this effect because this will help to design drugs to block or stimulate this response. If we can regulate the release of noradrenaline – which is absolutely fundamental for brain function - then this could have important implications for the treatment of major health problems such as stress, blood pressure, pain and depression.”
Astrocytes, small non-neuronal star-shaped cells in the brain and spinal cord, are the principle source of brain lactate. The discovery that astrocytes communicate directly with neurones opens up a whole new area of pharmacology which has been little explored.
(Source: bristol.ac.uk)
Surgical implants are widely used in modern medicine but their effectiveness is often compromised by how our bodies react to them. Now, scientists at the University of Cambridge have discovered that implant stiffness is a major cause of this so-called foreign body reaction.
This is the first time that stiffness of implant materials has been shown to be involved in foreign body reactions. The findings – published in the journal Biomaterials – could lead to major improvements in surgical implants and the quality of life of patients whose lives depend on them.
Foreign bodies often trigger a process that begins with inflammation and ends with the foreign body being encapsulated with scar tissue. When this happens after an accident or injury, the process is usually vital to healing, but when the same occurs around, for example, electrodes implanted in the brain to alleviate tremor in Parkinson’s disease, it may be problematic.
Despite decades of research, the process remains poorly understood as neither the materials from which these implants are made, nor their electrical properties, can explain what triggers inflammation.
Instead of looking for classical biological causes, a group of Cambridge physicists, engineers, chemists, clinical scientists and biologists decided to take a different tack and examine the impact of an implant’s stiffness on the inflammatory process.
According to Dr Kristian Franze, one of the authors of the study: “Electrodes that are implanted in the brain, for example, should be chemically inert, and these foreign body reactions occur whether or not these electrodes are switched on, so it’s not the electrical signalling.
“We thought that an obvious difference between electrodes and brain tissue is stiffness. Brain tissue is as soft as cream cheese, it is one of the softest tissues in the body, and electrodes are orders of magnitude stiffer.”
To test their hypothesis that mechanical signals trigger inflammation, the team cultured brain cells on two different substrates. The substrates were chemically identical but one was as soft as brain tissue and the other two orders of magnitude stiffer, akin to the stiffness of muscle tissue.
When they examined the cells, they found major differences in their shape. “The cells grown on the stiffer substrate were very flat, whereas those grown on the soft substrate looked much more like cells you find in the brain,” he explained.
To confirm the findings they did genetic and other tests, which revealed that many of the inflammatory genes and proteins known to be involved in foreign body reactions had been upregulated on stiff surfaces.
The team then implanted a tiny foreign body into rats’ brains. The implant was made of a single material but one side was as soft as brain tissue and the other as stiff as muscle. They found much greater foreign body reaction around the stiff part of the implant.
“This strongly indicates that stiffness of a material may trigger foreign body reactions. It does not mean there aren’t other triggers, but stiffness definitely contributes and this is something new that hasn’t been known before,” he said.
The findings could have major implications for the design of implants used in the brain and other parts of the body.
“While it may eventually be possible to make implants out of new, much softer materials, our results suggest that in the short term, simply coating existing implants with materials that match the stiffness of the tissue they are being implanted into will help reduce foreign body reactions,” said Dr Franze.
New evidence that chronic stress predisposes brain to mental illness
University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life.
Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events.
Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell.
How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel.
In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain.
“We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said.
The hippocampus regulates memory and emotions, and plays a role in various emotional disorders.
Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry.
Does stress affect brain connectivity?
Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses.
“You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.”
She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life.
Stress tweaks stem cells
Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells.
The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections.
The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said.
Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones.
Image caption: New details about how motor neurons die in ALS have been uncovered by a new cell-culture system that combines spinal cord or brain cells from ALS patients with human motor neurons. The culture system shows that patient astrocytes (shown here with a blue-stained nucleus) release a toxin that kills motor neurons via a recently discovered process described as a “controlled cellular explosion.” Image: Diane Re.
Toxin from Brain Cells Triggers Neuron Loss in Human ALS Model
In most cases of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, a toxin released by cells that normally nurture neurons in the brain and spinal cord can trigger loss of the nerve cells affected in the disease, Columbia researchers reported today in the online edition of the journal Neuron.
The toxin is produced by star-shaped cells called astrocytes and kills nearby motor neurons. In ALS, the death of motor neurons causes a loss of control over muscles required for movement, breathing, and swallowing. Paralysis and death usually occur within 3 years of the appearance of first symptoms.
The report follows the researchers’ previous study, which found similar results in mice with a rare, genetic form of the disease, as well as in a separate study from another group that used astrocytes derived from patient neural progenitor cells. The current study shows that the toxins are also present in astrocytes taken directly from ALS patients.
“I think this is probably the best evidence we can get that what we see in mouse models of the disease is also happening in human patients,” said the study’s senior author, Serge Przedborski, MD, PhD, the Page and William Black Professor of Neurology (in Pathology and Cell Biology), Vice Chair for Research in the department of Neurology, and co-director of Columbia’s Motor Neuron Center.
The findings also are significant because they apply to the most common form of ALS, which affects about 90 percent of patients. Scientists do not know why ALS develops in these patients; the other 10 percent of patients carry one of 27 genes known to cause the disease.
“Now that we know that the toxin is common to most patients, it gives us an impetus to track down this factor and learn how it kills the motor neurons,” Dr. Przedborski said. “Its identification has the potential to reveal new ways to slow down or stop the destruction of the motor neurons.”
In the study, Dr. Przedborski and study co-authors Diane Re, PhD, and Virginia Le Verche, PhD, associate research scientists, removed astrocytes from the brain and spinal cords of six ALS patients shortly after death and placed the cells in petri dishes next to healthy motor neurons. Because motor neurons cannot be removed from human subjects, they had been generated from human embryonic stem cells in the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, also at CUMC.
Within two weeks, many of the motor neurons had shrunk and their cell membranes had disintegrated; about half of the motor neurons in the dish had died. Astrocytes removed from people who died from causes other than ALS had no effect on the motor neurons. Nor did other types of cells taken from ALS patients.
The researchers confirmed that the cause of the motor neurons’ death was a toxin released into the environment by immersing healthy motor neurons in the astrocytes’ culture media. The presence of the media, even without astrocytes, killed the motor neurons.
How the Toxin Triggers Motor Neuron Death
The researchers have not yet identified the toxin released by the astrocytes. But they did discover the nature of the neuronal death process triggered by the toxin.The toxin triggers a biochemical cascade in the motor neurons that essentially causes them to undergo a controlled cellular explosion.
Drs. Przedborski, Re, and Le Verche found that they could prevent astrocyte-triggered motor neuron death by inhibiting one of the key components of this molecular cascade.
These findings may lead to a way to prevent motor neuron death in patients and potentially prolong life. But the therapeutic potential of such inhibition is far from clear. “For example, we don’t know if this would leave patients with living but dysfunctional neurons,” Dr. Przedborski said. The researchers are now testing the idea of inhibition in animal models of ALS.
New Human Cell Model of ALS Will Speed Identification of Potential Therapies
The development of new therapies for ALS has been disappointing, with more than 30 clinical trials ending with no new treatments since the 1995 FDA approval of riluzole.
The lack of progress may be partly because animal models used to study ALS do not completely recreate the human disease. The new all-human cell model of ALS created for the current study may improve scientists’ ability to identify useful drug targets, particularly for the most common form of the disease.
“Although there are many neurodegenerative disorders, only for a handful do we have access to a simplified model that is relevant to the disease and can therefore potentially be used for high-throughput drug screening. So this model is quite special,” Dr. Przedborski said. “Here we have a spontaneous disease phenotype triggered by the relevant tissue that causes human illness. That’s one important thing. The other important thing is that this model is derived entirely from human elements. This is probably the closest, most natural model of human ALS that we can get in a dish.”