Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Scientists describe the genetic signature of a vital set of neurons
Scientists at NYU Langone Medical Center have identified two genes involved in establishing the neuronal circuits required for breathing. They report their findings in a study published in the December issue of Nature Neuroscience. The discovery, featured on the journal’s cover, could help advance treatments for spinal cord injuries and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), which gradually kill neurons that control the movement of muscles needed to breathe, move, and eat.
The study identifies a molecular code that distinguishes a group of muscle-controlling nerve cells collectively known as the phrenic motor column (PMC). These cells lie about halfway up the back of the neck, just above the fourth cervical vertebra, and are “probably the most important motor neurons in your body,” says Jeremy Dasen, PhD, assistant professor of physiology and neuroscience and a member of the Howard Hughes Medical Institute, who led the three-year study with Polyxeni Philippidou, PhD, a postdoctoral fellow.
Harming the part of the spinal cord where the PMC resides can instantly shut down breathing. But relatively little is known about what distinguishes PMC neurons from neighboring neurons, and how PMC neurons develop and wire themselves to the diaphragm in the fetus.
The PMC cells relay a constant flow of electrochemical signals down their bundled axons and onto the diaphragm muscles, allowing the lungs to expand and relax in the natural rhythm of breathing. “We now have a set of molecular markers that distinguish those cells from other populations of motor neurons, so that we can study them in detail and look for ways to selectively enhance their survival,” Dr. Dasen says. Degeneration of PMC neurons is the primary cause of death in patients with ALS and spinal cord injuries.
To find out what distinguishes PMC neurons from their spinal neighbors in mice, Dr. Philippidou injected a retrograde fluorescent tracer into the phrenic nerve, which wires the PMC to the diaphragm, and then looked for the spinal neurons that lit up as the tracer worked its way back to the PMC. He used transgenic mice that express green fluorescent protein (GFP) in motor neurons and their axons in order to see the phrenic nerve. After noting the characteristic gene expression pattern of these PMC neurons, Dr. Philippidou began to determine their specific roles. Ultimately, a complicated strain of transgenic mice, based partly on mice supplied by collaborator Lucie Jeannotte, PhD, at the University of Laval in Quebec, revealed two genes, Hoxa5 and Hoxc5, as the prime controllers of proper PMC development. Hox genes (39 are expressed in humans) are well known as master gene regulators of animal development.
When Hoxa5 and Hoxc5 are silenced in embryonic motor neurons in mice, the scientists reported, the PMC fails to form its usual, tightly columnar organization and doesn’t connect correctly to the diaphragm, leaving a newborn animal unable to breathe. “Even if you delete these genes late in fetal development, the PMC neuron population drops and the phrenic nerve doesn’t form enough branches on diaphragm muscles,” Dr. Dasen says.
Dr. Dasen plans to use the findings to help understand the wider circuitry of breathing—including rhythm-generating neurons in the brain stem, which are in turn responsive to carbon dioxide levels, stress, and other environmental factors. “Now that we know something about PMC cells, we can work our way through the broader circuit, to try to figure out how all those connections are established,” he says.
"Once we understand how the respiratory network is wired we can begin to develop novel treatment options for breathing disorders such as sleep apneas," adds Dr. Philippidou.
In late October Dr. Dasen lost many of his transgenic mice when Hurricane Sandy flooded the basement of the Smilow building at NYU Langone Medical Center. But just before the hurricane hit, he sent an important group of these mice back to Dr. Jeannotte in Quebec, “so we didn’t lose everything,” he says.
(Source: eurekalert.org)
Biking Restores Brain Connectivity in Parkinson’s
PROBLEM: It’s commonly known that Parkinson’s Disease is a chronic, progressive, disease of central nervous system that affects motor ability — its recognizable early stages are characterized by shakiness and difficulty walking. No cure exists, which is why back in 2003, the best Dr. Jay Alberts of the Cleveland Clinic Lerner Research Institute rode a tandem bicycle across Iowa with a Parkinson’s patient (to raise awareness). Unexpectedly, the patient showed improvements in her condition after the trip. In what now much be common lore at the Institute, Alberts attempted to explain the inexplicable by noticing that his own pace was faster than that of his partner, who was forced, by the cruel mechanics of tandem cycling, to pedal faster in order to keep up.
METHODOLOGY: Alberts and his colleagues used functional connectivity MRI to study the brains of 26 patients with Parkinson’s Disease before and after they engaged in an 8-week exercise program and then, as a follow-up, one month later. Three times a week, the patients worked out on stationary bicycles. The experimental group used a modified bike that, using an algorithm in the place of a super in-shape doctor, would measure their rate of exertion and use it as a basis to push them harder than they would otherwise choose.
RESULTS: What the researchers referred to as “forced rate activity,” others might feel is more accurately labeled “torture.” But when they calculated the brain activation of the patients forced to pedal past their comfort level, they found lasting increases in connectivity between two areas of the brain responsible for motor ability: the primary motor cortex and the posterior region of the thalamus.
CONCLUSION: Forced-rate bicycle exercise appears to be an effective therapy for Parkinson’s disease.
IMPLICATION: The treatment delivered dramatic results, and has the distinction of being inexpensive and accessible. Alberts contends that even those without access to their own algorithm for forced-rate activity may be able to see improvement by using an at-home stationary bike. The next step is to evaluate the possible effects of other forms of exercise, like swimming.
The full study was presented at the annual meeting of the Radiological Society of North America.
Researchers find chemical ‘switches’ for neurodegenerative diseases
By using a model, researchers at the University of Montreal have identified and “switched off” a chemical chain that causes neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis and dementia. The findings could one day be of particular therapeutic benefit to Huntington’s disease patients. “We’ve identified a new way to protect neurons that express mutant huntingtin proteins,” explained Dr. Alex Parker of the University of Montreal’s Department of Pathology and Cell Biology and its affiliated CRCHUM Research Centre. A cardinal feature of Huntington’s disease – a fatal genetic disease that typically affects patients in midlife and causes progressive death of specific areas of the brain – is the aggregation of mutant huntingtin protein in cells. “Our model revealed that increasing another cell chemical called progranulin reduced the death of neurons by combating the accumulation of the mutant proteins. Furthermore, this approach may protect against neurodegenerative diseases other than Huntington’s disease.”
There is no cure for Huntingdon’s disease and current strategies show only modest benefits, and a component of the protein aggregates involved are also present in other degenerative diseases. “My team and I wondered if the proteins in question, TDP-43 and FUS, were just innocent bystanders or if they affected the toxicity caused by mutant huntingtin,” Dr. Parker said. To answer this question, Dr. Parker and University of Montreal doctoral student Arnaud Tauffenberger turned to a simple genetic model based on the expression of mutant huntingtin in the nervous system of the transparent roundworm C. elegans. A large number of human disease genes are conserved in worms, and C. elegans in particular enables researchers to rapidly conduct genetic analyses that would not be possible in mammals.
Dr. Parker’s team found that deleting the TDP-43 and FUS genes, which produce the proteins of the same name, reduced neurodegeneration caused by mutant huntingtin. They then confirmed their findings in the cell of a mammal cell, again by using models. The next step was then to determining how neuroprotection works. TDP-43 targets a chemical called progranulin, a protein linked to dementia. “We demonstrated that removing progranulin from either worms or cells enhanced huntingtin toxicity, but increasing progranulin reduced cell death in mammalian neurons. This points towards progranulin as a potent neuroprotective agent against mutant huntingtin neurodegeneration,” Dr. Parker said. The researchers will need to do further testing this in more complex biological models to determine if the same chemical switches work in all mammals. If they do, then progranulin treatment may slow disease onset or progression in Huntington’s disease patients.
(Source: eurekalert.org)
Yeast Protein Breaks up Amyloid Fibrils and Disordered Protein Clumps In Different Ways
Several fatal brain disorders, including Parkinson’s disease, are connected by the misfolding of specific proteins into disordered clumps and stable, insoluble fibrils called amyloid. Amyloid fibrils are hard to break up due to their stable, ordered structure. For example, a-synuclein forms amyloid fibrils that accumulate in Lewy Bodies in Parkinson’s disease. By contrast, protein clumps that accumulate in response to environmental stress, such as heat shock, possess a less stable, disordered architecture.
Hsp104, an enzyme from yeast, breaks up both amyloid fibrils and disordered clumps. In the most recent issue of Cell, James Shorter, PhD, assistant professor of Biochemistry and Biophysics, and colleagues from the Perelman School of Medicine, University of Pennsylvania, show that Hsp104 switches mechanism to break up amyloid versus disordered clumps. For stable amyloid-type structures, Hsp104 needs all six of its subunits, which together make a hexamer, to pull the clumps apart. By contrast, for the more amorphous, non-amyloid clumps, Hsp104 required only one of its six subunits.
Reconsidering cancer’s bad guy
Researchers at the University of Copenhagen have found that a protein, known for causing cancer cells to spread around the body, is also one of the molecules that trigger repair processes in the brain. These findings are the subject of a paper, published this week in Nature Communications. They point the way to new avenues of research into degenerative brain diseases like Alzheimer’s.
How to repair brain injuries is a fundamental question facing brain researchers. Scientists have been familiar with the protein S100A4 for some time as a factor in metastasis, or how cancer spreads. However it’s the first time the protein has been shown to play a role in brain protection and repair.
“This protein is not normally in the brain, only when there’s trauma or degeneration. When we deleted the protein in mice we discovered that their brains were less protected and able to resist injury. We also discovered that S100A4 works by activating signalling pathways inside neurons,” says Postdoc Oksana Dmytriyeva, who worked on the research in a team at the Protein Laboratory in the Department of Neuroscience and Pharmacology at the University of Copenhagen.
The villain turns out to be the hero
This research stands on the shoulders of many years of work on S100A4 in its deadlier role in cancer progression. The discovery represents a significant development for the new Neuro-Oncology Group that moved to the University of Copenhagen’s Protein Laboratory Group from the Danish Cancer Society in October.
“We were surprised to find this protein in this role, as we thought it was purely a cancer protein. We are very excited about it and we’re looking forward to continuing our research in a practical direction. We hope that the findings will eventually benefit people who need treatment for neurodegenerative disorders like Alzheimer’s disease, although obviously we have a long way to go before we get to that point,” says Oksana Dmytriyeva.
(Source: news.ku.dk)
Parkinson’s Disease Protein Causes Disease Spread and Neuron Death in Healthy Animals
Understanding how any disease progresses is one of the first and most important steps towards finding treatments to stop it. This has been the case for such brain-degenerating conditions as Alzheimer’s disease. Now, after several years of incremental study, researchers at the Perelman School of Medicine, University of Pennsylvania have been able to piece together important steps in how Parkinson’s disease (PD) spreads from cell to cell and leads to nerve cell death.
Their line of research also informs the general concept that this type of disease progression is a common pathway for such other neurodegenerative diseases as Alzheimer’s, Huntington’s, progressive supranuclear palsy, and possibly amyotrophic lateral sclerosis (ALS).
The Penn team found that injecting synthetic, misfolded and fibrillar α-Synuclein (α-Syn) – the PD disease protein — into the brains of normal, “wild-type” mice recapitulates the cascade of cellular demise seen in human PD patients.
Parkinson’s disease is characterized by abundant α-Syn clumps in neurons and the massive loss of midbrain dopamine-producing neurons. However, a cause-and-effect relationship between the formation of α-Syn clumps and neurodegeneration has been unclear.
In short, the Penn researchers found that, in healthy mice, a single injection of synthetic, misfolded α-Syn fibrils led to a cell-to-cell transmission of pathologic α-Syn proteins and the formation of Parkinson’s α-Syn clumps known as Lewy bodies in interconnected regions of the brain. Their findings appear in this week’s issue of Science. The team was led by senior author Virginia M.-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine, and first author Kelvin C. Luk, PhD, research assistant professor in the CNDR.
Neurons made from stem cells drive brain activity after transplantation in laboratory model
Researchers and patients look forward to the day when stem cells might be used to replace dying brain cells in Alzheimer’s disease and other neurodegenerative conditions. Scientists are currently able to make neurons and other brain cells from stem cells, but getting these neurons to properly function when transplanted to the host has proven to be more difficult. Now, researchers at Sanford-Burnham Medical Research Institute have found a way to stimulate stem cell-derived neurons to direct cognitive function after transplantation to an existing neural network. The study was published November 7 in the Journal of Neuroscience.
“We showed for the first time that embryonic stem cells that we’ve programmed to become neurons can integrate into existing brain circuits and fire patterns of electrical activity that are critical for consciousness and neural network activity,” said Stuart A. Lipton, M.D., Ph.D., senior author of the study. Lipton is director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.
The trick turned out to be light. Lipton and his team—including Juan Piña-Crespo, Ph.D., D.V.M., Maria Talantova, M.D., Ph.D., and other colleagues at Sanford-Burnham and Stanford University—transplanted human stem cell-derived neurons into a rodent hippocampus, the brain’s information-processing center. Then they specifically activated the transplanted neurons with optogenetic stimulation, a relatively new technique that combines light and genetics to precisely control cellular behavior in living tissues or animals.
To determine if the newly transplanted, light-stimulated human neurons were actually working, Lipton and his team measured high-frequency oscillations in existing neurons at a distance from the transplanted ones. They found that the transplanted neurons triggered the existing neurons to fire high-frequency oscillations. Faster neuronal oscillations are usually better—they’re associated with enhanced performance in sensory-motor and cognitive tasks.
To sum it up, the transplanted human neurons not only conducted electrical impulses, they also roused neighboring neuronal networks into firing—at roughly the same rate they would in a normal, functioning hippocampus.
The therapeutic outlook for this technology looks promising. “Based on these results, we might be able to restore brain activity—and thus restore motor and cognitive function—by transplanting easily manipulated neuronal cells derived from embryonic stem cells,” Lipton said.
(Source: beaker.sanfordburnham.org)
Key protein interactions involved in neurodegenerative disease revealed
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).
The study was published online ahead of print on November 8, 2012, by the journal Structure.
The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration.
"Our findings have long-range implications for drug discovery," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate competitive inhibitors for this enzyme with even greater specificity and hopefully less toxicity."
The scientists used what they called structure class analysis, looking at groups of structures, which revealed subtle differences not apparent looking at them individually.
"From a structural point of view, these different proteins appear to be very similar, but the biochemistry shows that the results of their binding to JNK were very different," he said.
LoGrasso and his colleagues were responsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis.
All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell’s fate.
"Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them."
(Source: medicalxpress.com)
Hunting neuron killers in Alzheimer’s and TBI
Sanford-Burnham researchers discovered that the protein appoptosin prompts neurons to commit suicide in several neurological conditions—giving them a new therapeutic target for Alzheimer’s disease and traumatic brain injury.
Dying neurons lead to cognitive impairment and memory loss in patients with neurodegenerative disorders–conditions like Alzheimer’s disease and traumatic brain injury. To better diagnose and treat these neurological conditions, scientists first need to better understand the underlying causes of neuronal death.
Enter Huaxi Xu, Ph.D., professor in Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center. He and his team have been studying the protein appoptosin and its role in neurodegenerative disorders for the past several years. Appoptosin levels in the brain skyrocket in conditions like Alzheimer’s and stroke, and especially following traumatic brain injury.
Appoptosin is known for its role in helping the body make heme, the molecule that carries iron in our blood (think “hemoglobin,” which makes blood red). But what does heme have to do with dying brain cells? As Xu and his group explain in a paper they published recently in the Journal of Neuroscience, excess heme leads to the overproduction of reactive oxygen species, which include cell-damaging free radicals and peroxides, and triggers apoptosis, the carefully regulated process of cellular suicide. This means that more appoptosin and more heme cause neurons to die.
Not only did Xu and his team unravel this whole appoptosin-heme-neurodegeneration mechanism, but when they inhibited appoptosin in laboratory cell cultures, they noticed that the cells didn’t die. This finding suggests that appoptosin might make an interesting new therapeutic target for neurodegenerative disorders.
What’s next? Xu and colleagues are now probing appoptosin’s function in mouse models. They’re also looking for new therapies that target the protein.
“Since the upregulation of appoptosin is important for cell death in diseases such as Alzheimer’s, we’re now searching for small molecules that modulate appoptosin expression or activity. We’ll then determine whether these compounds may be potential drugs for Alzheimer’s or other neurodegenerative diseases,” Xu explains.
Putting a stop to runaway appoptosin won’t be easy, though. That’s because we still need the heme-building protein to operate at normal levels for our blood to carry iron. In a previous study, researchers found that a mutation in the gene that encodes appoptosin causes anemia. “Too much of anything is bad, but so is too little,” Xu says.
New therapies that target neurodegenerative disorders and traumatic brain injury are sorely needed. According to the CDC, approximately 1.7 million people sustain a traumatic brain injury each year. It’s an acute injury, but one that can also lead to long-term problems, causing epilepsy and increasing a person’s risk for Alzheimer’s and Parkinson’s diseases. Not only has traumatic brain injury become a worrisome problem in youth and professional sports in recent years, the Department of Defense calls traumatic brain injury “one of the signature injuries of troops wounded in Afghanistan and Iraq.”
(Source: beaker.sanfordburnham.org)
Feel-good hormone helps to jog the memory
The feel-good hormone dopamine improves long-term memory. This is the finding of a team lead by Emrah Düzel, neuroscientist at the German Center for Neurodegenerative Diseases (DZNE) and the University of Magdeburg. The researchers investigated test subjects ranging in age from 65 to 75 years, who were given a precursor of dopamine. Treated subjects performed better in a memory test than a comparison group, who had taken a placebo. The study provides new insights into the formation of long lasting memories and also has implications for understanding why memories fade more rapidly following the onset of Alzheimer’s disease. The results appear in the Journal of Neuroscience.