Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Brainpower applied to understanding of neural stem cells
How do humans and other mammals get so brainy? USC researcher Wange Lu and his colleagues shed new light on this question in a paper published in the journal Cell Reports on Oct. 24.
The researchers donned their thinking caps to explain how neural stem and progenitor cells differentiate into neurons and related cells called glia. Neurons transmit information through electrical and chemical signals; glia surround, support and protect neurons in the brain and throughout the nervous system. Glia do everything from holding neurons in place to supplying them with nutrients and oxygen to protect them from pathogens.
By studying the embryo neural stem cells of mice in a petri dish, Lu and his colleagues discovered that a protein called SMEK1 promotes the differentiation of neural stem and progenitor cells. At the same time, SMEK1 keeps these cells in check by suppressing their uncontrolled proliferation.
The researchers also determined that SMEK1 doesn’t act alone: It works in concert with Protein Phosphatase 4 to suppress the activity of PAR3, a third protein that discourages neurogenesis — the birth of new neurons. With PAR3 out of the picture, neural stem cells and progenitors are free to differentiate into new neurons and glia.
“These studies reveal the mechanisms of how the brain keeps the balance of stem cells and neurons when the brain is formed,” said Wange Lu, associate professor of biochemistry and molecular biology at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “If this process goes wrong, it leads to cancer or mental retardation or other neurological diseases.”
Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step toward harnessing the cells’ therapeutic potential. This could offer new hope for patients with Alzheimer’s, Parkinson’s and many other currently incurable diseases.
The pig, the fish and the jellyfish: Tracing nervous disorders in humans
What do pigs, jellyfish and zebrafish have in common? It might be hard to discern the connection, but the different species are all pieces in a puzzle. A puzzle which is itself part of a larger picture of solving the riddles of diseases in humans.
The pig, the jellyfish and the zebrafish are being used by scientists at Aarhus University to, among other things, gain a greater understanding of hereditary forms of diseases affecting the nervous system. This can be disorders like Parkinson’s disease, Alzheimer’s disease, autism, epilepsy and the motor neurone disease ALS.
In a project, which has just finished, the scientists have focussed on a specific gene in pigs. The gene, SYN1, encodes the protein synapsin, which is involved in communication between nerve cells. Synapsin almost exclusively occurs in nerve cells in the brain. Parts of the gene can thus be used to control an expression of genes connected to hereditary versions of the aforementioned disorders.
The pig
The SYN1 gene can, with its specific expression in nerve cells, be used for generation of pig models of neurodegenerative diseases like Parkinson’s. The reason scientists bring a pig into the equation is that the pig is well suited as a model for investigating human diseases.
- Pigs are very like humans in their size, genetics, anatomy and physiology. There are plenty of them, so they are easily obtainable for research purposes, and it is ethically easier to use them than, for example, apes, says senior scientist Knud Larsen from Aarhus University.
Before the gene was transferred from humans to pigs, the scientists had to ensure that the SYN1 gene was only expressed in nerve cells. This was where the zebra fish entered the equation.
The zebrafish and the jellyfish
- The zebrafish is, as a model organism, the darling of researchers, because it is transparent and easy to genetically modify. We thus attached the relevant gene, SYN1, to a gene from a jellyfish (GFP), and put it into a zebrafish in order to test the specificity of the gene, explains Knud Larsen.
This is because jellyfish contain a gene that enables them to light up. This gene was transferred to the zebrafish alongside SYN1, so that the scientists could follow where in the fish activity occurred as a result of the SYN1 gene.
- We could clearly see that the transparent zebrafish shone green in its nervous system as a result of the SYN1 gene from humans initiating processes in the nervous system. We could thus conclude that SYN1 works specifically in nerve cells, says Knud Larsen.
The results of this investigation pave the way for the SYN1 gene being used in pig models for research into human diseases. The pig with the human gene SYN1 can presumably also be used for research into the development of the brain and nervous system in the foetus.
- I think it is interesting that the nervous system is so well preserved, from an evolutionary point of view, that you can observe a nerve-cell-specific expression of a pig gene in a zebrafish. It is impressive that something that works in a pig also works in a fish, says Knud Larsen.
Read the scientific article here.
Brain may flush out toxins during sleep
NIH-funded study suggests sleep clears brain of molecules associated with neurodegeneration
A good night’s rest may literally clear the mind. Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH.
“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.
For centuries, scientists and philosophers have wondered why people sleep and how it affects the brain. Only recently have scientists shown that sleep is important for storing memories. In this study, Dr. Nedergaard and her colleagues unexpectedly found that sleep may be also be the period when the brain cleanses itself of toxic molecules.
Their results, published in Science, show that during sleep a “plumbing” system, called the glymphatic system, may open, letting fluid flow rapidly through brain. Dr. Nedergaard’s lab recently discovered the glymphatic system helps control whether cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord, flows through the brain.
“It’s as if Dr. Nedergaard and her colleagues have uncovered a network of hidden caves and these exciting results highlight the potential importance of the network in normal brain function,” said Roderick Corriveau, Ph.D., a program director at NINDS.
Initially the researchers studied the system by injecting dye into the CSF of mice and watching it flow through their brains while simultaneously monitoring electrical brain activity. The dye flowed rapidly when the mice were unconscious, either asleep or anesthetized. In contrast, the dye barely flowed when the same mice were awake.
“We were surprised by how little flow there was into the brain when the mice were awake,” said Dr. Nedergaard. “It suggested that the space between brain cells changed greatly between conscious and unconscious states.”
To test this idea, the researchers inserted electrodes into the brain to directly measure the space between brain cells. They found that the space inside the brains increased by 60 percent when the mice were asleep or anesthetized.
“These are some dramatic changes in extracellular space,” said Charles Nicholson, Ph.D., a professor at New York University’s Langone Medical Center and an expert in measuring the dynamics of brain fluid flow and how it influences nerve cell communication.
Certain brain cells, called glia, control flow through the glymphatic system by shrinking or swelling. Noradrenaline is an arousing hormone that is also known to control cell volume. Treating awake mice with drugs that block noradrenaline induced sleep and increased brain fluid flow and the space between cells, further supporting the link between the glymphatic system and sleep.
Previous studies suggest that toxic molecules involved in neurodegenerative disorders accumulate in the space between brain cells. In this study, the researchers tested whether the glymphatic system controls this by injecting mice with radiolabeled beta-amyloid, a protein associated with Alzheimer’s disease, and measuring how long it lasted in their brains when they were asleep or awake. Beta-amyloid disappeared faster in mice brains when the mice were asleep, suggesting sleep normally clears toxic molecules from the brain.
“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, Ph.D., a program director at NINDS. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.”
The results may also highlight the importance of sleep.
“We need sleep. It cleans up the brain,” said Dr. Nedergaard.
(Source: ninds.nih.gov)
Brain scans show unusual activity in retired American football players
A new study has discovered profound abnormalities in brain activity in a group of retired American football players
Although the former players in the study were not diagnosed with any neurological condition, brain imaging tests revealed unusual activity that correlated with how many times they had left the field with a head injury during their careers.
Previous research has found that former American football players experience higher rates of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The new findings, published in Scientific Reports, suggest that players also face a risk of subtle neurological deficits that don’t show up on normal clinical tests.
Hidden problems
The study involved 13 former National Football League (NFL) professionals who believed they were suffering from neurological problems affecting their everyday lives as a consequence of their careers.
The former players and 60 healthy volunteers were given a test that involved rearranging coloured balls in a series of tubes in as few steps as possible. Their brain activity was measured using functional magnetic resonance imaging (fMRI) while they did the test.
The NFL group performed worse on the test than the healthy volunteers, but the difference was modest. More strikingly, the scans showed unusual patterns of brain activity in the frontal lobe. The difference between the two groups was so marked that a computer programme learned to distinguish NFL alumni and controls at close to 90 per cent accuracy based just on their frontal lobe activation patterns.
“The NFL alumni showed some of the most pronounced abnormalities in brain activity that I have ever seen, and I have processed a lot of patient data sets in the past,” said Dr Adam Hampshire, lead author of the study, from the Department of Medicine at Imperial College London.
The frontal lobe is responsible for executive functions: higher-order brain activity that regulates other cognitive processes. The researchers think the differences seen in this study reflect deficits in executive function that might affect the person’s ability to plan and organise their everyday lives.
“The critical fact is that the level of brain abnormality correlates strongly with the measure of head impacts of great enough severity to warrant being taken out of play. This means that it is highly likely that damage caused by blows to the head accumulate towards an executive impairment in later life.”
Early detection
Dr Hampshire and his colleagues at the University of Western Ontario, Canada suggest that fMRI could be used to reveal potential neurological problems in American football players that aren’t picked up by standard clinical tests. Brain imaging results could be useful to retired players who are negotiating compensation for neurological problems that may be related to their careers. Players could also be scanned each season to detect problems early.
The findings also highlight the inadequacy of standard cognitive tests for detecting certain types of behavioural deficit.
“Researchers have put a lot of time into developing tests to pick up on executive dysfunction, but none of them work at all well. It’s not unusual for an individual who has had a blow to the head to perform relatively well on a neuropsychological testing battery, and then go on to struggle in everyday life.
“The results tell us something very interesting about the human brain, which is that after damage, it can work harder and bring extra areas on line in order to cope with cognitive tasks. It is likely that in more complicated real world scenarios, this plasticity is insufficient and consequently, the executive impairment is no longer masked. In this respect, the results are also of relevance to other patients who suffer from multiple head injuries.
“Of course, this is a relatively preliminary study. We really need to test more players and to track players across seasons using brain imaging.”
"Smart glasses" can improve gait of Parkinson’s patients
A new app for intelligent glasses, such as Google Glass, will soon make it possible to improve the gait of patients suffering from Parkinson’s disease and to decrease their risk of falling. Researchers at the University of Twente’s MIRA Institute have received a grant from the NutsOhra fund for the development of the app.
The gait of Parkinson’s patients is often disturbed: sometimes this presents as a shuffling movement with the patient taking small steps, or it may result in the patient constantly looking for additional support. Gait disturbance also increases the chance of a fall, despite the progress made in terms of medication. Researchers have established that the gait of patients improves when they regularly see or hear a pattern. Examples might include stripes on the floor, or the regular ticking of a metronome.
The researchers, working under the leadership of Prof. Richard van Wezel, who is professor of Neurophysiology at the UT and is also attached to the Donders Institute in Nijmegen, are now looking at exploring the possibility of using the intelligent glasses, such as Google Glass, that are now coming on to the consumer market.
Intelligent glasses would be able to provide patients with the regular visual or audible patterns required. These patterns may take the form of moving stripes or shapes which the patient sees through the glasses, flashing shapes, or music with varying tempos. The latest intelligent glasses already have inbuilt cameras and accelerometers. By using these, it will be possible to determine which approach works best for each individual patient.
The MIRA Institute for Biomedical Technology and Technical Medicine is working on the project together with the Donders Institute for Brain, Cognition and Behaviour (Nijmegen), the Medisch Spectrum Twente hospital and the VUmc University Medical Centre in Amsterdam.
"Fonds NutsOhra", a fund that provides financial support for healthcare projects, has granted the sum of € 94,000 to the project.
How Exercise Beefs Up the Brain
While our muscles pump iron, our cells pump out something else: molecules that help maintain a healthy brain. But scientists have struggled to account for the well-known mental benefits of exercise, from counteracting depression and aging to fighting Alzheimer’s and Parkinson’s disease. Now, a research team may have finally found a molecular link between a workout and a healthy brain.
Much exercise research focuses on the parts of our body that do the heavy lifting. Muscle cells ramp up production of a protein called FNDC5 during a workout. A fragment of this protein, known as irisin, gets lopped off and released into the bloodstream, where it drives the formation of brown fat cells, thought to protect against diseases such as diabetes and obesity. (White fat cells are traditionally the villains.)
While studying the effects of FNDC5 in muscles, cellular biologist Bruce Spiegelman of Harvard Medical School in Boston happened upon some startling results: Mice that did not produce a so-called co-activator of FNDC5 production, known as PGC-1α, were hyperactive and had tiny holes in certain parts of their brains. Other studies showed that FNDC5 and PGC-1α are present in the brain, not just the muscles, and that both might play a role in the development of neurons.
Spiegelman and his colleagues suspected that FNDC5 (and the irisin created from it) was responsible for exercise-induced benefits to the brain—in particular, increased levels of a crucial protein called brain-derived neurotrophic factor (BDNF), which is essential for maintaining healthy neurons and creating new ones. These functions are crucial to staving off neurological diseases, including Alzheimer’s and Parkinson’s. And the link between exercise and BDNF is widely accepted. “The phenomenon has been established over the course of, easily, the last decade,” says neuroscientist Barbara Hempstead of Weill Cornell Medical College in New York City, who was not involved in the new work. “It’s just, we didn’t understand the mechanism.”
To sort out that mechanism, Spiegelman and his colleagues performed a series of experiments in living mice and cultured mouse brain cells. First, they put mice on a 30-day endurance training regimen. They didn’t have to coerce their subjects, because running is part of a mouse’s natural foraging behavior. “It’s harder to get them to lift weights,” Spiegelman notes. The mice with access to a running wheel ran the equivalent of a 5K every night.
Aside from physical differences between wheel-trained mice and sedentary ones—“they just look a little bit more like a couch potato,” says co-author Christiane Wrann, also of Harvard Medical School, of the latter’s plumper figures—the groups also showed neurological differences. The runners had more FNDC5 in their hippocampus, an area of the brain responsible for learning and memory.
Using mouse brain cells developing in a dish, the group next showed that increasing the levels of the co-activator PGC-1α boosts FNDC5 production, which in turn drives BDNF genes to produce more of the vital neuron-forming BDNF protein. They report these results online today in Cell Metabolism. Spiegelman says it was surprising to find that the molecular process in neurons mirrors what happens in muscles as we exercise. “What was weird is the same pathway is induced in the brain,” he says, “and as you know, with exercise, the brain does not move.”
So how is the brain getting the signal to make BDNF? Some have theorized that neural activity during exercise (as we coordinate our body movements, for example) accounts for changes in the brain. But it’s also possible that factors outside the brain, like those proteins secreted from muscle cells, are the driving force. To test whether irisin created elsewhere in the body can still drive BDNF production in the brain, the group injected a virus into the mouse’s bloodstream that causes the liver to produce and secrete elevated levels of irisin. They saw the same effect as in exercise: increased BDNF levels in the hippocampus. This suggests that irisin could be capable of passing the blood-brain barrier, or that it regulates some other (unknown) molecule that crosses into the brain, Spiegelman says.
Hempstead calls the findings “very exciting,” and believes this research finally begins to explain how exercise relates to BDNF and other so-called neurotrophins that keep the brain healthy. “I think it answers the question that most of us have posed in our own heads for many years.”
The effect of liver-produced irisin on the brain is a “pretty cool and somewhat surprising finding,” says Pontus Boström, a diabetes researcher at the Karolinska Institute in Sweden. But Boström, who was among the first scientists to identify irisin in muscle tissue, says the work doesn’t answer a fundamental question: How much of exercise’s BDNF-promoting effects come from irisin reaching the brain from muscle cells via the bloodstream, and how much are from irisin created in the brain?
Though the authors point out that other important regulator proteins likely play a role in driving BDNF and other brain-nourishing factors, they are focusing on the benefits of irisin and hope to develop an injectable form of FNDC5 as a potential treatment for neurological diseases and to improve brain health with aging.
Scientists identify protein linking exercise to brain health
A protein that is increased by endurance exercise has been isolated and given to non-exercising mice, in which it turned on genes that promote brain health and encourage the growth of new nerves involved in learning and memory, report scientists from Dana-Farber Cancer Institute and Harvard Medical School.
The findings, reported in the journal Cell Metabolism, help explain the well-known capacity of endurance exercise to improve cognitive function, particularly in older people. If the protein can be made in a stable form and developed into a drug, it might lead to improved therapies for cognitive decline in older people and slow the toll of neurodegenerative diseases such Alzheimer’s and Parkinson’s, according to the investigators.
“What is exciting is that a natural substance can be given in the bloodstream that can mimic some of the effects of endurance exercise on the brain,” said Bruce Spiegelman, PhD, of Dana-Farber and HMS. He is co-senior author of the publication with Michael E. Greenberg, PhD, chair of neurobiology at HMS.
The Spiegelman group previously reported that the protein, called FNDC5, is produced by muscular exertion and is released into the bloodstream as a variant called irisin. In the new research, endurance exercise – mice voluntarily running on a wheel for 30 days – increased the activity of a metabolic regulatory molecule, PGC-1α, in muscles, which spurred a rise in FNDC5 protein. The increase of FNDC5 in turn boosted the expression of a brain-health protein, BDNF (brain-derived neurotrophic protein) in the dentate gyrus of the hippocampus, a part of the brain involved in learning and memory.
It has been found that exercise stimulates BDNF in the hippocampus, one of only two areas of the adult brain that can generate new nerve cells. BDNF promotes development of new nerves and synapses – connections between nerves that allow learning and memory to be stored – and helps preserve the survival of brain cells.
How exercise raises BDNF activity in the brain wasn’t known; the new findings linking exercise, PGC-1α, FNDC5 and BDNF provide a molecular pathway for the effect, although Spiegelman and his colleagues suggest there are probably others.
Having shown that FNDC5 is a molecular link between exercise and increased BDNF in the brain, the scientists asked whether artificially increasing FNDC5 in the absence of exercise would have the same effect. They used a harmless virus to deliver the protein to mice through the bloodstream, in hopes the FNDC5 could reach the brain and raise BDNF activity. Seven days later, they examined the mouse brains and observed a significant increase in BDNF in the hippocampus.
“Perhaps the most exciting result overall is that peripheral deliver of FNDC5 with adenoviral vectors is sufficient to induce central expression of Bdnf and other genes with potential neuroprotective functions or those involved in learning and memory,” the authors said. Spiegelman cautioned that further research is needed to determine whether giving FNDC5 actually improves cognitive function in the animals. The scientists also aren’t sure whether the protein that got into the brain is FNDC5 itself, or irisin, or perhaps another variant of the protein.
Spiegelman said that development of irisin as a drug will require creating a more stable form of the protein.
(Source: dana-farber.org)
New Strategy to Treat Multiple Sclerosis Shows Promise in Mice
Scientists at The Scripps Research Institute (TSRI) have identified a set of compounds that may be used to treat multiple sclerosis (MS) in a new way. Unlike existing MS therapies that suppress the immune system, the compounds boost a population of progenitor cells that can in turn repair MS-damaged nerve fibers.
One of the newly identified compounds, a Parkinson’s disease drug called benztropine, was highly effective in treating a standard model of MS in mice, both alone and in combination with existing MS therapies.
“We’re excited about these results, and are now considering how to design an initial clinical trial,” said Luke L. Lairson, an assistant professor of chemistry at TSRI and a senior author of the study, which is reported online in Nature on October 9, 2013.
Lairson cautioned that benztropine is a drug with dose-related adverse side effects, and has yet to be proven effective at a safe dose in human MS patients. “People shouldn’t start using it off-label for MS,” he said.
A New Approach
An autoimmune disease of the brain and spinal cord, MS currently affects more than half a million people in North America and Europe, and more than two million worldwide. Its precise triggers are unknown, but certain infections and a lack of vitamin D are thought to be risk factors. The disease is much more common among those of Northern European heritage, and occurs about twice as often in women as in men.
In MS, immune cells known as T cells infiltrate the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating called myelin on some nerve fibers. As nerve fibers lose this myelin coating, they lose their ability to transmit signals efficiently, and in time may begin to degenerate. The resulting symptoms, which commonly occur in a stop-start, “relapsing-remitting” pattern, may include limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression, among other problems.
Current therapies, such as interferon beta, aim to suppress the immune attack that de-myelinates nerve fibers. But they are only partially effective and are apt to have significant adverse side effects.
In the new study, Lairson and his colleagues decided to try a complementary approach, aimed at restoring a population of progenitor cells called oligodendrocytes. These cells normally keep the myelin sheaths of nerve fibers in good repair and in principle could fix these coatings after MS damages them. But oligodendrocyte numbers decline sharply in MS, due to a still-mysterious problem with the stem-like precursor cells that produce them. “Oligodendrocyte precursor cells (OPCs) are present during progressive phases of MS, but for unknown reasons don’t mature into functional oligodendrocytes,” Lairson said.
A 100,000-Molecule Screen
Using a sophisticated small-molecule screening laboratory that TSRI manages in conjunction with the California Institute of Regenerative Medicine and in collaboration with the California Institute for Biomedical Research (Calibr), Lairson and his team screened a library of about 100,000 diverse compounds for any that could potently induce OPCs to mature or “differentiate.”
Several compounds scored well as OPC differentiation-inducers. Most were compounds of unknown activity —but one, benztropine, had been well characterized and indeed was already FDA-approved for treating Parkinson’s disease. “That was a surprise, and it meant that we could move forward relatively quickly in testing it,” said graduate student Vishal A. Deshmukh, first author of the paper who performed most of these experiments.
With the help of Brian R. Lawson, a senior author of the paper and assistant professor of immunology at TSRI, and his colleague Research Associate Virginie Tardif, Deshmukh set up tests of benztropine in mice with an induced MS-like autoimmune disease—a model commonly used for testing prospective MS drugs.
In these tests, benztropine showed a powerful ability to prevent autoimmune disease and also was effective in treating it after symptoms had arisen—virtually eliminating the disease’s ability to relapse. Although benztropine on its own worked about as well as existing treatments, it also showed a remarkable ability to complement these existing treatments, in particular two first-line immune-suppressant therapies, interferon-beta and fingolimod.
“Adding even a suboptimal level of benztropine effectively allowed us, for example, to cut the dose of fingolimod by 90%—and achieve the same disease-modifying effect as a normal dose of fingolimod,” said Lawson. “In a clinical setting that dose-lowering could translate into a big reduction in fingolimod’s potentially serious side effects.”
In further analyses, the researchers confirmed that benztropine works against disease in this mouse model by boosting the population of mature oligodendrocytes, which in turn restore the myelin sheaths of damaged nerves—even as the immune attack continues. “The benztropine-treated mice showed no change in the usual signs of inflammation, yet their myelin was mostly intact, suggesting that it was probably being repaired as rapidly as it was being destroyed,” said Lawson.
Benztropine is known to have multiple specific effects on brain cells, including the blocking of activity at acetylcholine and histamine receptors and a boosting of activity at dopamine receptors. But Lairson and his colleagues found evidence that the drug stimulates OPCs to differentiate mainly by blocking M1 or M3 acetylcholine receptors on these cells.
In addition to setting up initial clinical trials, Lairson and his team hope to learn more about how benztropine induces OPC maturation, and how its molecular structure might be optimized for this purpose. “We’re also looking at some of the other, relatively unknown molecules that we identified in our initial screen, to see if any of those has better clinical potential than benztropine,” he said.
“This work, like our previous studies with hematopoietic and mesenchymal stem cells, illustrates the power of small molecules to control stem and precursor cells in ways that may ultimately lead to a new generation of drugs for regenerative medicine,” said Peter G. Schultz, the Scripps Family Chair Professor in the Department of Chemistry at TSRI and one of the study’s senior authors.
Everything in moderation: excessive nerve cell pruning leads to disease
Scientists at the Montreal Neurological Institute and Hospital-The Neuro, McGill University, have made important discoveries about a cellular process that occurs during normal brain development and may play an important role in neurodegenerative diseases. The study’s findings, published in Cell Reports, a leading scientific journal, point to new pathways and targets for novel therapies for Alzheimer’s, Parkinson’s, ALS and other neurodegenerative diseases that affect millions of people world-wide.
Research into neurodegenerative disease has traditionally concentrated on the death of nerve cell bodies. However, it is now certain that in most cases that nerve cell body death represents the final event of an extended disease process. Studies have shown that protecting cell bodies from death has no impact on disease progression whereas blocking preceding axon breakdown has a significant benefit. The new study by researchers at The Neuro shifts the focus to the loss or degeneration of axons, the nerve-cell ‘branches’ that receive and distribute neurochemical signals among neurons.
During early development, axons are pruned to ensure normal growth of the nervous system. Emerging evidence suggests that this pruning process becomes reactivated in neurodegenerative disease, leading to the aberrant loss of axons and dendrites. Axonal pruning in development is significantly influenced by proteins called caspases. “The idea that caspases are even involved in axonal degeneration during development is very recent” said Dr. Philip Barker, a principal investigator at The Neuro and senior author of the study.
Dr. Barker and his colleagues show that the activity of certain ’executioner’ caspases (caspase-3 and caspase-9) induce axonal degeneration and that their action is suppressed by a protein termed XIAP (X-linked inhibitor of apoptosis). “We found that caspase-3- and -9 play crucial roles in axonal degeneration and that their activities are regulated by XIAP. XIAP acts as a brake on caspase activity and must be removed for degeneration to proceed” added Dr. Barker.
This balancing act between caspases and XIAP ensure that caspases do not cause unnecessary or excessive destruction. However, this balance may shift during neurodegenerative disease. “If we understand the pathways that regulate XIAP levels, we may be able to develop therapies that reduce caspase-dependent degeneration during neurodegenerative disease”.
(Source: mcgill.ca)
Study Identifies Possible Biomarker for Parkinson’s Disease
Researchers discover that an important clue to diagnosing Parkinson’s disease may lie just beneath the skin
Although Parkinson’s disease is the second most prevalent neurodegenerative disorder in the U.S., there are no standard clinical tests available to identify this widespread condition. As a result, Parkinson’s disease often goes unrecognized until late in its progression, when the brain’s affected neurons have already been destroyed and telltale motor symptoms such as tremor and rigidity have already appeared.
Now researchers from Beth Israel Deaconess Medical Center (BIDMC) have discovered that an important clue to diagnosing Parkinson’s may lie just beneath the skin.
In a study scheduled to appear in the October 29 print issue of the journal Neurology and currently published on-line, the investigators report that elevated levels of a protein called alpha-synuclein can be detected in the skin of Parkinson’s patients, findings that offer a possible biomarker to enable clinicians to identify and diagnose PD before the disease has reached an advanced stage.
Parkinson’s disease affects more than 1 million individuals throughout the U.S. Diagnosis is currently made through neurological history and examination, often by a patient’s primary care physician.
“Even the experts are wrong in diagnosing Parkinson’s disease a large percentage of the time,” says senior author Roy Freeman, MD, Director of the Autonomic and Peripheral Nerve Laboratory at BIDMC and Professor of Neurology at Harvard Medical School. “A reliable biomarker could help doctors in more accurately diagnosing Parkinson’s disease at an earlier stage and thereby offer patients therapies before the disease has progressed.”
Alpha-synuclein is a protein found throughout the nervous system. Although its function is unknown, it is the primary component of protein clumps known as Lewy bodies, which are considered the hallmark of Parkinson’s disease. There is accumulating evidence that the protein plays a role in Parkinson’s disease development.
“Alpha-synuclein deposition occurs early in the course of Parkinson’s disease and precedes the onset of clinical symptoms,” explains Freeman, who with his coauthors suspected that the protein was elevated in the skin’s structures with autonomic innervation.
“Symptoms related to the autonomic nervous system, including changes in bowel function, temperature regulation, and blood pressure control may antedate motor symptoms in Parkinson’s patients,” he explains. “Skin-related autonomic manifestations, including excessive and diminished sweating and changes in skin color and temperature, occur in almost two-thirds of patients with Parkinson’s disease. The skin can provide an accessible window to the nervous system and based on these clinical observations, we decided to test whether examination of the nerves in a skin biopsy could be used to identify a PD biomarker.”
To test this hypothesis, the research team enrolled 20 patients with Parkinson’s disease and 14 control subjects of similar age and gender. The participants underwent examinations, autonomic testing and skin biopsies in three locations on the leg. Alpha-synuclein deposition and density of cutaneous sensory, sudomotor and pilomotor nerve fibers were measured.
As predicted, their results showed that alpha-synuclein was increased in the cutaneous nerves supplying the sweat glands and pilomotor muscles in the Parkinson’s patients. Higher alpha-synuclein deposition in the nerves supplying the skin’s autonomic structures was associated with more advanced Parkinson’s disease and worsening autonomic function.
“There is a strong and unmet need for a biomarker for Parkinson’s disease,” says Freeman. “Alpha-synuclein deposition within the skin has the potential to provide a safe, accessible and repeatable biomarker. Our next steps will be to test whether this protein is present in the cutaneous nerves of individuals at risk for Parkinson’s disease, and whether measurement of alpha-synuclein deposition in the skin can differentiate Parkinson’s disease from other neurodegenerative disorders.”
(Source: newswise.com)