Posts tagged nerve cells
Articles and news from the latest research reports.
Melatonin delays ALS symptom onset and death in mice
Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study by researchers at the University of Pittsburgh School of Medicine. In a report published online ahead of print in the journal Neurobiology of Disease, the team revealed that receptors for melatonin are found in the nerve cells, a finding that could launch novel therapeutic approaches.
Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles, said senior investigator Robert Friedlander, M.D., UPMC Endowed Professor of neurosurgery and neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But the causes of the condition are not well understood, thwarting development of a cure or even effective treatments.
Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than a thousand FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.
"Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS," Dr. Friedlander said. "We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases."
Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer, and had less degeneration of motor neurons in the spinal cord.
"Much more work has to be done to unravel these mechanisms before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment," Dr. Friedlander said. "I suspect that a combination of agents that act on these pathways will be needed to make headway with this devastating disease."
(Source: eurekalert.org)
Scientists identify important regulator for synapse stability and plasticity
Using the fruit fly as a model organism, neurobiologists from the Friedrich Miescher Institute for Biomedical Research have identified the L1-type CAM neuroglian as an important regulator for synapse growth, function and stability. They show that the interaction of neuroglian with ankyrin provides a regulatory module to locally control synaptic connectivity and function.
A Drosophila neuromuscular junction. Motoneuron membrane (blue), synaptic vesicles (green), postsynaptic density (red)
From its earliest beginnings until an organism’s death, the nervous system changes. Connections between nerve cells are formed, stabilized and disassembled not only during the development of the brain in the womb and in early childhood, but also in adults as they learn or form memories. In this flow of change, cell adhesion molecules (CAMs), which mediate cell-cell interactions, are thought to provide stability and guidance in a Velcro-like-manner as synapses change.
Jan Pielage and his group at the Friedrich Miescher Institute for Biomedical Research have carried out an unbiased genetic screen to identify cell adhesion molecules that control synapse maintenance and plasticity, using the fruit fly, Drosophila. As they publish in the latest issue of PLOS Biology, they identified the cell adhesion molecule called neuroglian as a key regulator for synapse stability.
Neuroglian is a transmembrane protein with a large extracellular domain and an intracellular signaling domain. Through the extracellular domain interactions with CAMs on neighboring cells are established. This stabilizes the site and is a prerequisite for synapse formation. “We think that the extracellular interactions of neuroglian are essential for neurite outgrowth and axon targeting during early development,” explains Pielage.
The scientists could then show that the intracellular domain, which interacts with the adaptor molecule called ankyrin, modulates the stability of synapses. At the neuromuscular junction, where nerve cells innervate the muscle, the strength of the interaction of neuroglian with ankyrin modulates the balance between synapse growth and stability. As the binding affinity of ankyrin for neuroglian decreased, e.g. due to phosphorylation, the mobility of neuroglian within the motorneuron increased. This change in mobility caused the destabilization of synapses but at the same time, it allowed the formation of new synapses at other places. “This organization permits easy regulation, and allows the fine tuning of synaptic connectivity along one nerve cell without disrupting the neuronal network or impairing overall circuit stability,” said Pielage.
In the central nervous system, where synapses are formed between two neurons, a homophilic interaction of neuroglian is required to establish the contact between pre- and postsynaptic neurons. A differential regulation of ankyrin binding is then necessary to coordinate transsynaptic development and to enable synapse maturation and function. “Modulation of the neuroglian-ankyrin interaction might enable local and precise control of synaptic connectivity,” comments Pielage.
This comprehensive structure function study provides a molecular basis for previous observations linking mutations in the ankyrin binding domain of the human homologue of neuroglian, L1CAM, to neurological L1/CRASH disorders that include mental retardation.
(Source: fmi.ch)
New research findings on the brain’s guardian cells
Researcher Johan Jakobsson and his colleagues have now published their results in Nature Communications.
At present, researchers know very little about exactly how microglia work. At the same time, there is a lot of curiosity and high hopes among brain researchers that greater understanding of microglia could lead to entirely new drug development strategies for various brain diseases”, says Johan Jakobsson, research group leader at the Division of Molecular Neurogenetics at Lund University.
What the researchers have now succeeded in identifying is a deviation in the structure of the microglia cells, which makes it possible to visualise them and study their behaviour. By inserting a luminescent protein controlled by a microscopic molecule, microRNA-9, the researchers can now distinguish the microglia and monitor their function over time in the brains of rats and mice.
It has long been known that microglia form the first line of defence of the immune system in diseases of the brain. They move quickly to the affected area and release an arsenal of molecules that protect the nerve cells and clear away damaged tissue.
New research also suggests that microglia not only guard the nerve cells but also play an important role in their basic function.
“This represents a real step forward in technological development. Now we can view microglia in a way that has not been possible before. We and our colleagues now hope to be able to use this technique to study the role of the cells in different disease models, for example Parkinson’s disease and stroke, in which microglia are believed to play an important role”, explains Johan Jakobsson.
Mapping The Brain Onto The Mind
BRAIN initiative aims to improve tools for studying neurons to answer questions about human thought and behavior
The images appearing on the computer screen were almost too detailed and fast-moving to take in, Misha B. Ahrens remembers. He and colleague Philipp J. Keller were recording the activity of about 80,000 neurons in a live zebrafish brain, the first time something on this scale had been done. Cross-sectional pictures of the young fish’s head flew by, dotted with splotches of light.
The Howard Hughes Medical Institute (HHMI) neuroscientists were using a zebrafish larva with a fluorescent protein inserted in its neurons, and the protein was lighting up every time the cells fired. Their custom-built microscope imaged and recorded the resulting lightning storm in the fish’s brain in real time.
Ahrens commemorated the milestone experiment—which took place nearly seven months ago in a lab at the institute’s Janelia Farm Research Campus outside Washington, D.C.—by filming it with his iPhone. “It was mind-blowing to see the entire brain flash past our eyes,” he remembers.
Keller sat in awe at the computer, repeatedly pulling up and admiring slices of data the high-speed apparatus was collecting. The translucent zebrafish, immobilized in a glass tube filled with gel and nestled among the microscope’s optics, was completely unaware that its neural processing was causing such a stir.
Up until that point, scientists had been able to record simultaneous activity from only about 2 to 3% of the 100,000 neurons in a young zebrafish’s head, Keller says. He and Ahrens managed to capture 80%—a giant leap for fishkind.
On March 18, the duo reported their brain-imaging feat online at Nature Methods. Just 15 days later, President Barack Obama announced a large-scale neuroscience initiative to study the dynamics of brain circuits (C&EN, April 8, page 9).
Unlike the Human Connectome Project—a federal program that strives to uncover a static map of the brain’s circuits—this new initiative aims to uncover those circuits’ activity and interplay. BRAIN (Brain Research through Advancing Innovative Neurotechnologies), as the project is called, will get $100 million in federal support if Obama’s request is granted (see page 25), and it will get a similar amount from private foundations such as HHMI in 2014.
“It was a coincidence,” Keller says of the timing of the proposal. He and Ahrens weren’t involved in developing BRAIN, but their goal—to record all the activity from all the neurons in a simple organism’s brain at once—falls directly in line with the initiative.
Eighty-thousand neurons is a lot. But it’s nothing compared with the 85 billion nerve cells that humans have in their brains, or even the 75 million that mice have. To make the leap to measuring large swaths of the brain circuits of rodents or even humans, BRAIN researchers will need to develop new methods of measuring neuronal activity. They are already working on molecular tags to more accurately indicate nerve cell firing in real time. And scientists are developing miniaturized probes to monitor brain cells without disturbing the organ itself, as well as faster techniques for analyzing the flood of data generated by such a huge number of neurons.
Some imaging methods that monitor multitudes of neurons, like that of Ahrens and Keller, already exist. As do techniques for probing scads of nerve cells with tiny electrodes. BRAIN will likely build on these technologies, experts say. But it will also shoot to build “dream” technologies such as implantable nanomaterials that transmit the activity of individual neurons from inside the head.
At the moment, however, no one knows the exact scope of BRAIN. The National Institutes of Health has already appointed a team of neuroscientists to draw up a blueprint for what should be a multiyear initiative. Other federal agencies involved—the National Science Foundation and the Defense Advanced Research Projects Agency—have yet to announce their strategies.
“Neuroscience is getting to the point where researchers cannot take the next big step to understand neural circuits armed with traditional technology,” says Rafael Yuste, a neuron-imaging expert at Columbia University.
And taking that step, he argues, is vital to understanding human thought. “We have a suspicion that the brain is an emerging system,” Yuste says. In other words, how the brain produces memories or actions involves the interactions of all its neurons, rather than just one or even 1,000. It’s like watching television, Yuste adds. “You need to see all the pixels, or at least most of them, to figure out what’s playing.”
Along with five other scientists, Yuste made the original pitch for a public-private project to map the brain’s dynamics in a 2012 article in Neuron. The group argued that not only could this approach help reveal how the human mind works, but it might also offer some insight into what happens when the brain malfunctions. Knowing how the brain’s circuits are supposed to function, Yuste says, could help pinpoint what’s going wrong in conditions such as schizophrenia, which likely involve faulty circuitry.
BRAIN proponents also say areas outside of science and medicine could profit from the initiative. If successful, they claim, BRAIN could yield economic benefits similar to the Human Genome Project, a program launched in 1990 to sequence all the base pairs in a person’s DNA. “Every dollar we spent to map the human genome has returned $140 to our economy,” President Obama noted when he announced BRAIN.
As was the case for the Human Genome Project, BRAIN has been criticized by many scientists. In an already-tight fiscal climate, some researchers have voiced worries that paying for the initiative will mean losing their own funds. And others have expressed reservations that the project is going after too many neurons to yield interpretable, useful results.
But no one seems to dispute that better tools to record activity from nerve cells is a worthwhile goal. “There’s definitely room to grow in many of the techniques we use to record brain activity,” says Mark J. Schnitzer, a neuroscientist at Stanford University. So far, he says, progress has been made mainly by individual labs doing their own thing. But to get to the next level more rapidly, a coordinated effort like BRAIN—centers and labs of neuroscientists, chemists, and researchers in other disciplines working together—might be the ticket.
Until recently, the number of neurons being recorded simultaneously in experiments was doubling every seven years, according to a 2011 review in Nature Neuroscience. But the Janelia team blew this trend out of the water with its high-speed camera and microscope, which rapidly illuminates and images slices of the brain.
The Janelia experiment worked primarily because zebrafish larvae are transparent to light and can be easily immobilized without negative consequences to their brain activity. But moving to mice, which have more neurons and a light-impenetrable skull, will require some more serious innovation, Keller adds.
Some researchers have designed implantable prisms and fiber-optic probes to direct light into the depths of the mouse brain. But those optical tricks are still limited to measuring a few hundred neurons at once. Plus, the mouse has to be tethered to the fibers or prevented from moving altogether.
Stanford’s Schnitzer has overcome the mobility issue with a miniaturized microscope that he and his team designed to fit onto a mouse’s head. Standing three-quarters of an inch tall, the lightweight device, which contains its own light source and camera, gets implanted into the rodent’s brain, enabling researchers to track the freely moving animal’s nerve cell activity.
Early this year, Schnitzer’s group used the setup to follow the dynamics of roughly 1,000 neurons in a mouse’s brain for more than a month (Nat. Neurosci., DOI: 10.1038/nn.3329). The team learned that neurons in one part of the mouse’s brain fired in similar patterns whenever the mouse returned to a familiar spot in its enclosure.
Still, such optical techniques are invasive. “The most elegant experiment would be done from the outside, without mechanical disturbance to the brain,” Columbia’s Yuste says. He’d like to see BRAIN help develop new light sources that can penetrate farther into brain tissue than a few millimeters.
Also on Yuste’s neuron-imaging wish list is a better way to indicate cell firing. As in the Janelia experiment and Schnitzer’s microscope study, the imaging of neuronal activity is typically carried out with calcium indicators. These are molecules that move to the insides of neurons or are proteins engineered to reside there, both designed to fluoresce when they bind to calcium ions.
As a nerve cell fires, its ion channels open, allowing calcium ions to trickle inside and trigger the indicators.
However, “calcium imaging is flawed,” Yuste says. “It’s an indirect method of tracking neuronal firing.” The indicators can’t tell scientists whether a nerve cell fired a little or a lot, he argues. And they don’t track the cells’ electrical activity in real time because calcium diffusion and binding are comparatively slow.
So Yuste and others are working to develop dyes or nanomaterials, called voltage indicators, that bind within a neuron’s membrane and optically signal the cell’s electrical status. Progress is slow-going, however, because a cell’s membrane can hold only so many indicators on its surface and the resulting signal is low.
Another way neuroscientists are more directly measuring nerve cells’ electrical activity is with miniaturized electrodes and nanowires. These probes measure, at submillisecond speeds, the electrical current emitted by a neuron when it fires.
“But anytime you plunge anything into the brain, you have to worry about tissue damage,” says Sotiris Masmanidis, a neurobiologist at the University of California, Los Angeles. “The concern is, how much are you perturbing the system you’re studying?”
To minimize tissue disturbance, Masmanidis and others are lithographically fabricating arrays of microelectrodes that can record nerve cells’ electrical signals from 50 to 100 µm away. So far, the UCLA researcher says, electrode arrays are capable of measuring, at most, 100 to 1,000 neurons at a time.
Determining what types of nerve cells an arrayed microelectrode is measuring, however, is not exactly straightforward, given that it blindly measures any neuron in its vicinity, Masmanidis says. To figure it out, scientists have to take extra steps and monitor the cells’ reaction to drugs or other modulators.
But what good is measuring the dynamics of a slew of nerve cells without having any idea why they’re firing? BRAIN supporters think one way of getting an answer to which environmental cues or perceptions trigger certain neuronal activity patterns is a technique called optogenetics.
Hailed by Nature Methods as the “method of the year” in 2010, optogenetics enables scientists to activate particular nerve cells in the brains of animals with light. The researchers first engineer light-activated proteins into a mouse’s neurons and then trigger the macromolecules via fiber-optic arrays implanted in the rodent’s brain.
Once researchers have measured a firing pattern from an animal’s nerve cells, they can later play it back to see what happens, says Edward S. Boyden, an optogenetics pioneer and neurobiologist at Massachusetts Institute of Technology. “Once we ‘dial’ an activity pattern into the brain,” he says, “if we see that it’s enough to drive some behavior, that could be quite powerful for understanding which parts of the brain drive specific functions.”
Researchers have already been optogenetically stimulating clusters of a few hundred cells in mice, investigating the rodents’ decision-making abilities and aggressive tendencies.
But a brain is more than just electrical activity, says Anne M. Andrews, a psychiatry professor at UCLA. It also uses at least 100 types of neurotransmitters that are involved in triggering neuronal activity at cell junctions, or synapses. “If we want to understand how information is encoded in neuronal signaling, we have to study chemical neurotransmission at the level of synapses,” Andrews says.
And what better way to do that than with nanotechnology? asks Paul S. Weiss, a chemist and nanoscience expert, also at UCLA. After all, the junctions between neurons are just 10 nm wide, he adds.
Andrews and Weiss are hoping BRAIN will support the development of nanoscale sensors to measure the chemical activity at synapses. And they’re already in talks with UCLA’s Masmanidis to functionalize channels on his microelectrodes with molecules that could sense neurotransmitters.
No matter what BRAIN ends up encompassing, one thing is clear: Advances in the numbers of neurons monitored will necessitate improvements in data analysis and storage.
Take, for instance, the experiment done at Janelia. That single session of recording from a zebrafish brain generated 1 terabyte of data. “So you can fit two or three experiments on a computer hard drive,” Ahrens says. “It’s not a bottleneck yet, but when we start creating faster microscopes, computational power might become a problem.”
He and Keller also have just scratched the surface when it comes to analyzing the data they obtained from their initial experiments. As they reported in their Nature Methods paper, the pair found a circuit in the fish’s hindbrain functionally coupled to a specific part of its spinal cord. But determining what that means and what the rest of the brain is doing will require more study and help from computational neuroscientists.
Atrophy in key region of brain associated with multiple sclerosis
Magnetic resonance imaging (MRI) measurements of atrophy in an important area of the brain are an accurate predictor of multiple sclerosis (MS), according to a new study published online in the journal Radiology. According to the researchers, these atrophy measurements offer an improvement over current methods for evaluating patients at risk for MS.
MS develops as the body’s immune system attacks and damages myelin, the protective layer of fatty tissue that surrounds nerve cells within the brain and spinal cord. Symptoms include visual disturbances, muscle weakness and trouble with coordination and balance. People with severe cases can lose the ability to speak or walk.
Approximately 85 percent of people with MS suffer an initial, short-term neurological episode known as clinically isolated syndrome (CIS). A definitive MS diagnosis is based on a combination of factors, including medical history, neurological exams, development of a second clinical attack and detection of new and enlarging lesions with contrast-enhanced or T2-weighted MRI.
"For some time we’ve been trying to understand MRI biomarkers that predict MS development from the first onset of the disease," said Robert Zivadinov, M.D., Ph.D., FAAN, from the Buffalo Neuroimaging Analysis Center of the University at Buffalo in Buffalo, N.Y. "In the last couple of years, research has become much more focused on the thalamus."
The thalamus is a structure of gray matter deep within the brain that acts as a kind of relay center for nervous impulses. Recent studies found atrophy of the thalamus in all different MS disease types and detected thalamic volume loss in pediatric MS patients.
"Thalamic atrophy may become a hallmark of how we look at the disease and how we develop drugs to treat it," Dr. Zivadinov said.
For this study, Dr. Zivadinov and colleagues investigated the association between the development of thalamic atrophy and conversion to clinically definite MS.
"One of the most important reasons for the study was to understand which regions of the brain are most predictive of a second clinical attack," he said. "No one has really looked at this over the long term in a clinical trial."
The researchers used contrast-enhanced MRI for initial assessment of 216 CIS patients. They performed follow-up scans at six months, one year and two years. Over two years, 92 of 216 patients, or 42.6 percent, converted to clinically definite MS. Decreases in thalamic volume and increase in lateral ventricle volumes were the only MRI measures independently associated with the development of clinically definite MS.
"First, these results show that atrophy of the thalamus is associated with MS," Dr. Zivadinov said. "Second, they show that thalamic atrophy is a better predictor of clinically definite MS than accumulation of T2-weighted and contrast-enhanced lesions."
The findings suggest that measurement of thalamic atrophy and increase in ventricular size may help identify patients at high risk for conversion to clinically definite MS in future clinical trials involving CIS patients.
"Thalamic atrophy is an ideal MRI biomarker because it’s detectable at very early stage," Dr. Zivadinov said. "It has very good predictive value, and you will see it used more and more in the future."
The research team continues to follow the study group, with plans to publish results from the four-year follow-up next summer. They are also trying to learn more about the physiology of the thalamic involvement in MS.
"The next step is to look at where the lesions develop over two years with respect to the location of the atrophy," Dr. Zivadinov said. "Thalamic atrophy cannot be explained entirely by accumulation of lesions; there must be an independent component that leads to loss of thalamus."
MS affects more than 2 million people worldwide, according to the Multiple Sclerosis International Foundation. There is no cure, but early diagnosis and treatment can slow development of the disease.
(Source: eurekalert.org)
ALS trial shows novel therapy is safe
An investigational treatment for an inherited form of Lou Gehrig’s disease has passed an early phase clinical trial for safety, researchers at Washington University School of Medicine in St. Louis and Massachusetts General Hospital report.
The researchers have shown that the therapy produced no serious side effects in patients with the disease, also known as amyotrophic lateral sclerosis (ALS). The phase 1 trial’s results, available online in Lancet Neurology, also demonstrate that the drug was successfully introduced into the central nervous system.
The treatment uses a technique that shuts off the mutated gene that causes the disease. This approach had never been tested against a condition that damages nerve cells in the brain and spinal cord.
“These results let us move forward in the development of this treatment and also suggest that it’s time to think about applying this same approach to other mutated genes that cause central nervous system disorders,” says lead author Timothy Miller, MD, PhD, assistant professor of neurology at Washington University. “These could include some forms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other conditions.”
ALS destroys nerves that control muscles, gradually leading to paralysis and death. For treatment of the disease, the sole FDA-approved medication, Riluzole, has only a marginal effect.
Most cases of ALS are sporadic, but about 10 percent are linked to inherited mutations. Scientists have identified changes in 10 genes that can cause ALS and are still looking for others.
The study focused on a form of ALS caused by mutations in a gene called SOD1, which account for 2 percent of all ALS cases. Researchers have found more than 100 mutations in the SOD1 gene that cause ALS.
“At the molecular level, these mutations affect the properties of the SOD1 protein in a variety of ways, but they all lead to ALS,” says Miller, who is director of the Christopher Wells Hobler Lab for ALS Research at the Hope Center for Neurological Disorders at Washington University.
Rather than try to understand how each mutation causes ALS, Miller and his colleagues focused on blocking production of the SOD1 protein using a technique called antisense therapy.
To make a protein, cells have to copy the protein-building instructions from the gene. Antisense therapy blocks the cell from using these copies, allowing researchers to selectively silence individual genes.
“Antisense therapy has been considered and tested for a variety of disorders over the past several decades,” Miller says. “For example, the FDA recently approved an antisense therapy called Kynamro for familial hypercholesterolemia, an inherited condition that increases cholesterol levels in the blood.”
Miller and colleagues at the University of California-San Diego devised an antisense drug for SOD1 and successfully tested it in an animal model of the disease.
Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital, was co-PI of the phase I clinical safety trial described in the new paper. Clinicians at Barnes-Jewish Hospital, Massachusetts General Hospital, Johns Hopkins Hospital and the Methodist Neurological Institute in Houston gave antisense therapy or a placebo to 21 patients with SOD1-related ALS. Treatment consisted of spinal infusions that lasted 11 hours.
The scientists found no significant difference between side effects in the control and treatment groups. Headache and back pain, both of which are often associated with spinal infusion, were among the most common side effects.
Immediately after the injections, the researchers took spinal fluid samples. This let them confirm the antisense drug was circulating in the spinal fluid of patients who received the treatment.
To treat SOD1-related ALS in the upcoming phase II trial, researchers will need to increase the dosage of the antisense drug. As the dose rises, they will watch to ensure that the therapy does not cause harmful inflammation or other side effects as it lowers SOD1 protein levels.
“All the information that we have so far suggests lowering SOD1 will be safe,” Miller says. “In fact, completely disabling SOD1 in mice seems to have little to no effect. We think it will be OK in patients, but we won’t know for sure until we’ve conducted further trials.”
The therapy may one day be helpful in the more common, noninherited forms of ALS, some of which may be linked to problems with the SOD1 protein.
“Before we can consider using this same therapy for sporadic ALS, we need more evidence that SOD1 is a major contributor to these forms of the disorder,” Miller says.
The trial was conducted with support from ISIS Pharmaceuticals, which co-owns a patent on the SOD1 antisense drug.
New light shed on early stage Alzheimer’s disease
The disrupted metabolism of sugar, fat and calcium is part of the process that causes the death of neurons in Alzheimer’s disease. Researchers from Karolinska Institutet in Sweden have now shown, for the first time, how important parts of the nerve cell that are involved in the cell’s energy metabolism operate in the early stages of the disease. These somewhat surprising results shed new light on how neuronal metabolism relates to the development of the disease.
In the Alzheimer’s disease brain, plaques consisting of so called amyloid-beta-peptide (Aβ) are accumulated. It is also a well-known fact that the nerve cells of patients with Alzheimer’s disease have problems metabolising for example glucose and calcium, and that these disorders are associated with cell death. The metabolism of these substances is the job of the cell mitochondria, which serve as the cell’s power plant and supply the cell with energy.
However, for the mitochondria to do this, they need good contact with another part of the cell called the endoplasmic reticulum (ER). The specialised region of ER that is in contact with mitochondria is called the MAM region. Earlier studies on yeast and other types of cells have shown that the deactivation of certain proteins in the MAM region disrupt the contact points between the mitochondria and the ER, preventing the delivery of energy to the cell and causing cell death.
Now for the first time, researchers at Karolinska Institutet have studied the MAM region in nerve cells, and examined the interaction between the mitochondria and the ER in early stage Alzheimer’s disease. Although at this point in the development of the disease Aβ has not formed large, lumpy plaques, symptoms still appear, implying that Aβ that has not yet formed plaque is toxic to neurons.
The team’s results are slightly surprising. When nerve cells are exposed to low doses of Aβ, it leads to an increase in the number of contact points between the mitochondria and the ER, causing more calcium to be transferred from the ER to the mitochondria. The resulting over-accumulation of calcium is toxic to the mitochondria and affects their ability to supply energy to the nerve cell.
“It’s urgent that we find out what causes neuronal death if we’re to develop molecules that check the disease,” says Maria Ankarcrona, docent and researcher at the Department of Neurobiology, Care Sciences and Society, and the Alzheimer’s Disease Research Centre of Karolinska Institutet. “In the long run we might be able to produce a drug that can arrest the progress of the disease at a stage when the patient is still able to manage their daily lives. If we can extend that period by a number of years, we’d have made great gains. Today there are no drugs that affect the actual disease process.”
The researchers conducted their studies on mice bred to develop symptoms of Alzheimer’s disease. They also studied nerve cells from deceased Alzheimer’s patients and neurons cultivated in the laboratory.
(Source: alphagalileo.org)
Stem cell transplant restores memory, learning in mice
For the first time, human embryonic stem cells have been transformed into nerve cells that helped mice regain the ability to learn and remember.
A study at UW-Madison is the first to show that human stem cells can successfully implant themselves in the brain and then heal neurological deficits, says senior author Su-Chun Zhang, a professor of neuroscience and neurology.
Once inside the mouse brain, the implanted stem cells formed two common, vital types of neurons, which communicate with the chemicals GABA or acetylcholine. “These two neuron types are involved in many kinds of human behavior, emotions, learning, memory, addiction and many other psychiatric issues,” says Zhang.
The human embryonic stem cells were cultured in the lab, using chemicals that are known to promote development into nerve cells — a field that Zhang has helped pioneer for 15 years. The mice were a special strain that do not reject transplants from other species.
After the transplant, the mice scored significantly better on common tests of learning and memory in mice. For example, they were more adept in the water maze test, which challenged them to remember the location of a hidden platform in a pool.
The study began with deliberate damage to a part of the brain that is involved in learning and memory.
Three measures were critical to success, says Zhang: location, timing and purity. “Developing brain cells get their signals from the tissue that they reside in, and the location in the brain we chose directed these cells to form both GABA and cholinergic neurons.”
The initial destruction was in an area called the medial septum, which connects to the hippocampus by GABA and cholinergic neurons. “This circuitry is fundamental to our ability to learn and remember,” says Zhang.
The transplanted cells, however, were placed in the hippocampus — a vital memory center — at the other end of those memory circuits. After the transferred cells were implanted, in response to chemical directions from the brain, they started to specialize and connect to the appropriate cells in the hippocampus.
The process is akin to removing a section of telephone cable, Zhang says. If you can find the correct route, you could wire the replacement from either end.
For the study, published in the current issue of Nature Biotechnology, Zhang and first author Yan Liu, a postdoctoral associate at the Waisman Center on campus, chemically directed the human embryonic stem cells to begin differentiation into neural cells, and then injected those intermediate cells. Ushering the cells through partial specialization prevented the formation of unwanted cell types in the mice.
Ensuring that nearly all of the transplanted cells became neural cells was critical, Zhang says. “That means you are able to predict what the progeny will be, and for any future use in therapy, you reduce the chance of injecting stem cells that could form tumors. In many other transplant experiments, injecting early progenitor cells resulted in masses of cells — tumors. This didn’t happen in our case because the transplanted cells are pure and committed to a particular fate so that they do not generate anything else. We need to be sure we do not inject the seeds of cancer.”
Brain repair through cell replacement is a Holy Grail of stem cell transplant, and the two cell types are both critical to brain function, Zhang says. “Cholinergic neurons are involved in Alzheimer’s and Down syndrome, but GABA neurons are involved in many additional disorders, including schizophrenia, epilepsy, depression and addiction.”
Though tantalizing, stem-cell therapy is unlikely to be the immediate benefit. Zhang notes that “for many psychiatric disorders, you don’t know which part of the brain has gone wrong.” The new study, he says, is more likely to see immediate application in creating models for drug screening and discovery.
(Source: news.wisc.edu)
Science surprise: Toxic protein made in unusual way may explain brain disorder
A bizarre twist on the usual way proteins are made may explain mysterious symptoms in the grandparents of some children with mental disabilities.
The discovery, made by a team of scientists at the University of Michigan Medical School, may lead to better treatments for older adults with a recently discovered genetic condition.
The condition, called Fragile X-associated Tremor Ataxia Syndrome (FXTAS), causes shakiness and balance problems and is often misdiagnosed as Parkinson’s disease. The grandchildren of people with the disease have a separate disorder called Fragile X syndrome, caused by problems in the same gene. The new discovery may also help shine light on that disease, though indirectly.
In a new paper published in the journal Neuron, the U-M-led team presents evidence that a toxic protein they’ve named FMRpolyG contributes to the death of nerve cells in FXTAS – and that this protein is made in a very unusual way.
Normally, DNA is transcribed into RNA, and then a part of the RNA is translated into a protein that performs its function in cells. Where this translation process starts on the RNA is usually determined by a specific sequence called a start codon.
The gene mutation that causes FXTAS is a repeated DNA sequence that is made into RNA but normally is not made into protein because it lacks a start codon. However, the investigators discovered that when this repeat expands, it can trigger protein production by a new mechanism known as RAN translation.
Corresponding author Peter Todd, M.D., Ph.D., notes that this unusual translation process appears to stem from a long chain of repeated DNA “letters” found in the genes of both grandparents and kids with Fragile X mutations. Todd is the Bucky and Patti Harris Professor in the U-M Department of Neurology
"Essentially, we’ve found that a sequence of DNA which shouldn’t be made into protein is being made into protein – and that this causes a toxicity in nerve cells," he explains. "We believe that the protein forms aggregates, and that this is a major contributor to toxicity and symptoms in FXTAS."
The U-M group went on to show how this RAN translation occurs in FXTAS and demonstrated that blocking it prevents the repeat mutation from being toxic, suggesting a new target for future treatments.
Fragile X tremor/ataxia syndrome or FXTAS was only discovered a decade ago. It may affect as many as one in every 3,000 men and one in 20,000 women, who have a repeat mutation in the gene known as FMR1. However, these patients don’t usually develop symptoms until late middle age, allowing them to pass the mutation on to their daughters, who can then have children where the DNA repeat that has grown much longer. In those children, especially in boys, it can cause severe intellectual disability and autism-like symptoms as the FMR1 gene shuts down and none of the normal protein is produced.
In fact, says Todd, it’s often only after a child is diagnosed with Fragile X syndrome through genetic testing that their grandfather or grandmother finds out that their own symptoms stem from FXTAS. Doctors in U-M’s Neurogenetics clinic for adults, and the Pediatric Genetics Clinic at U-M’s C.S. Mott Children’s Hospital, routinely work together to address the needs of Fragile X families.
"We have some treatments for the symptoms that FXTAS patients have, but we do not yet have a cure," says Todd, who regularly sees patients with FXTAS and related disorders. "Better treatments are needed – and this new discovery might help lead to novel strategies for clearing away or preventing the buildup of this toxic protein."
In addition, he says, the discovery that Fragile X ataxia results in part from RAN translation could have significance both for other diseases like amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease) and certain forms of dementia that are caused by DNA repeats. It can also aid our understanding of basic biology. “This may represent a new way in which translational initiation events occur, and may have importance beyond this one disease,” he notes. Further research on how RAN translation occurs, and why, is needed.
The idea that proteins can be created without a “start site” flies in the face of what most students of biology have learned in the last century. “In biology, we’re finding that the rules we once thought were hard and fast have some wiggle room,” Todd says.
(Source: eurekalert.org)
Scientists reverse memory loss in animal brain cells
Neuroscientists at The University of Texas Health Science Center at Houston (UTHealth) have taken a major step in their efforts to help people with memory loss tied to brain disorders such as Alzheimer’s disease.
Using sea snail nerve cells, the scientists reversed memory loss by determining when the cells were primed for learning. The scientists were able to help the cells compensate for memory loss by retraining them through the use of optimized training schedules. Findings of this proof-of-principle study appear in the April 17 issue of The Journal of Neuroscience.
“Although much works remains to be done, we have demonstrated the feasibility of our new strategy to help overcome memory deficits,” said John “Jack” Byrne, Ph.D., the study’s senior author, as well as director of the W.M. Keck Center for the Neurobiology of Learning and Memory and chairman of the Department of Neurobiology and Anatomy at the UTHealth Medical School.
This latest study builds on Byrne’s 2012 investigation that pioneered this memory enhancement strategy. The 2012 study showed a significant increase in long-term memory in healthy sea snails called Aplysia californica, an animal that has a simple nervous system, but with cells having properties similar to other more advanced species including humans.
Yili Zhang, Ph.D., the study’s co-lead author and a research scientist at the UTHealth Medical School, has developed a sophisticated mathematical model that can predict when the biochemical processes in the snail’s brain are primed for learning.
Her model is based on five training sessions scheduled at different time intervals ranging from 5 to 50 minutes. It can generate 10,000 different schedules and identify the schedule most attuned to optimum learning.
“The logical follow-up question was whether you could use the same strategy to overcome a deficit in memory,” Byrne said. “Memory is due to a change in the strength of the connections among neurons. In many diseases associated with memory deficits, the change is blocked.”
To test whether their strategy would help with memory loss, Rong-Yu Liu, Ph.D., co-lead author and senior research scientist at the UTHealth Medical School, simulated a brain disorder in a cell culture by taking sensory cells from the sea snails and blocking the activity of a gene that produces a memory protein. This resulted in a significant impairment in the strength of the neurons’ connections, which is responsible for long-term memory.
To mimic training sessions, cells were administered a chemical at intervals prescribed by the mathematical model. After five training sessions, which like the earlier study were at irregular intervals, the strength of the connections returned to near normal in the impaired cells.
“This methodology may apply to humans if we can identify the same biochemical processes in humans. Our results suggest a new strategy for treatments of cognitive impairment. Mathematical models might help design therapies that optimize the combination of training protocols with traditional drug treatments,” Byrne said.
He added, “Combining these two could enhance the effectiveness of the latter while compensating at least in part for any limitations or undesirable side effects of drugs. These two approaches are likely to be more effective together than separately and may have broad generalities in treating individuals with learning and memory deficits.”
(Image courtesy: UC Berkeley)