Posts tagged neurodegeneration
Articles and news from the latest research reports.
Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein that is linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson’s, Alzheimer’s and autism.
"This receptor family is an exciting new target for future medicines for treatment of brain disorders," said P. Jeffrey Conn, PhD, Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery, who was a senior author of the study with Raymond Stevens, PhD, a professor in the Department of Integrative Structural and Computational Biology at TSRI. "This new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts."
The research—which focuses on the mGlu1 receptor—was reported in the March 6, 2014 issue of the journal Science.
A Family of Drug Targets
The mGlu1 receptor, which helps regulate the neurotransmitter glutamate, belongs to a superfamily of molecules known as G protein-coupled receptors (GPCRs).
GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters and light. After binding these molecules, GPCRs trigger a specific response inside the cell. More than one-third of therapeutic drugs target GPCRs—including allergy and heart medications, drugs that target the central nervous system and anti-depressants.
The Stevens lab’s work has revolved around determining the structure and function of GPCRs. GPCRs are not well understood and many fundamental breakthroughs are now occurring due to the understanding of GPCRs as complex machines, carefully regulated by cholesterol and sodium.
When the Stevens group decided to pursue the structure of mGlu1 and other key members of the mGlu family, it was natural the scientists reached out to the researchers at Vanderbilt. “They are the best in the world at understanding mGlu receptors,” said Stevens. “By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling.”
Colleen Niswender, PhD, director of Molecular Pharmacology and research associate professor of Pharmacology at the Vanderbilt Center for Neuroscience Drug Discovery, also thought the collaboration made sense. “This work leveraged the unique strengths of the Vanderbilt and Scripps teams in applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships to validate the receptor structure,” she said.
The Challenge of the Unknown
mGlu1 was a particularly challenging research topic.
In general, GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge. And the mGlu1 receptor is particularly tricky as, in addition to the domain spanning the membrane, it has a large domain extending into the extracellular space. Moreover, two copies of this multidomain receptor associating in a dimer are needed to transmit glutamate’s signal across the membrane.
The task was made more difficult because there was no template for mGlu1 from closely related GPCR proteins to guide the researchers.
“mGlu1 belongs to class C GPCRs, of which no structure has been solved before,” said TSRI graduate student Chong Wang, a first author of the new study with TSRI graduate student Huixian Wu. “This made the project much harder. We could not use other GPCRs as a template to design constructs for expression and stabilization or to help interpret diffraction data. The structure was so different that old school methods in novel protein structure determination had to be used.”
Surprising Results
The team decided to try to determine the structure of mGlu1 bound to novel “allosteric modulators” of mGlu1 contributed by the Vanderbilt group. Allosteric modulators bind to a site far away from the binding site of the natural activator (in this case, presumably the glutamate molecule), but change the shape of the molecule enough to affect receptor function. In the case of allosteric drug candidates, the hope is that the compounds affect the receptor function in a desirable, therapeutic way.
"Allosteric modulators are promising drug candidates as they can ‘fine-tune’ GPCR function,” said Karen Gregory, a former postdoctoral fellow at Vanderbilt University, now at Monash Institute of Pharmaceutical Sciences. “However, without a good idea of how drug-like compounds interact with the receptor to adjust the strength of the signal, discovery efforts are challenging."
The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu1 in complex with one of the drug candidates, as well as a deeper understanding of the receptor’s function and pharmacology.
The findings show that mGlu1 possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance.
“Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for the binding of allosteric modulators,” said Vsevolod “Seva” Katritch, assistant professor of molecular biology at TSRI and a co-author of the paper. “This is very important for understanding action of the allosteric modulator drugs and may partially explain difficulties in screening for such drugs.
“The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors,” he continued, “some of which are equally important in drug discovery.”
Experimental stroke drug also shows promise for people with Lou Gehrig’s disease
Keck School of Medicine of USC neuroscientists have unlocked a piece of the puzzle in the fight against Lou Gehrig’s disease, a debilitating neurological disorder that robs people of their motor skills. Their findings appear in the March 3, 2014, online edition of the Proceedings of the National Academy of Sciences of the United States of America, the official scientific journal of the U.S. National Academy of Sciences.
"We know that both people and transgenic rodents afflicted with this disease develop spontaneous breakdown of the blood-spinal cord barrier, but how these microscopic lesions affect the development of the disease has been unclear," said Berislav V. Zlokovic, M.D., Ph.D., the study’s principal investigator and director of the Zilkha Neurogenetic Institute at USC. "In this study, we show that early motor neuron dysfunction related to the disease in mice is proportional to the degree of damage to the blood-spinal cord barrier and that restoring the integrity of the barrier delays motor neuron degeneration. We are hopeful that we can apply these findings to the corresponding disease mechanism in people. "
In this study, Zlokovic and colleagues found that an experimental drug now being studied in human stroke patients appears to protect the blood-spinal cord barrier’s integrity in mice and delay motor neuron impairment and degeneration. The drug, an activated protein C analog called 3K3A-APC, was developed by Zlokovic’s start-up biotechnology company, ZZ Biotech.
Lou Gehrig’s disease, also called amyotrophic lateral sclerosis, or ALS, attacks motor neurons, which are cells that control the muscles. The progressive degeneration of the motor neurons in ALS eventually leads to paralysis and difficulty breathing, eating and swallowing.
According to The ALS Association, approximately 15 people in the United States are diagnosed with ALS every day. It is estimated that as many as 30,000 Americans live with the disease. Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 upon diagnosis. Life expectancy of an ALS patient averages about two to five years from the onset of symptoms.
ALS’s causes are not completely understood, and no cure has yet been found. Only one Food and Drug Administration-approved drug called riluzole has been shown to prolong life by two to three months. There are, however, devices and therapies that can manage the symptoms of the disease to help people maintain as much independence as possible and prolong survival.
Researchers reveal the dual role of brain glycogen
In 2007, in an article published in Nature Neuroscience, scientists at the Institute for Research in Biomedicine (IRB Barcelona) headed by Joan Guinovart, an authority on glycogen metabolism, suggested that in Lafora Disease (LD), a rare and fatal neurodegenerative condition that affects adolescents, neurons die as a result of the accumulation of glycogen—chains of glucose. They went on to propose that this accumulation is the root cause of this disease.
The breakthrough of this paper was two-sided: first, the researchers established a possible cause of LD and therefore were able to point to a plausible therapeutic target, and second, they discovered that neurons have the capacity to store glycogen—an observation that had never been made—and that this accumulation was toxic.
Other reports defended a different theory and upheld that the glycogen deposits were not cause by the neurodegeneration but were a consequence of another, more important, cell imbalance, such as a down deregulation of autophagy—the cell recycling and cleaning programme. In several articles, Guinovart’s “Metabolic engineering and diabetes therapy” group has recently brought to light evidence of the toxicity of glycogen deposits for LD patients, and has now provided irrefutable data.
In an article published at the beginning of February in Human Molecular Genetics, with the research associate Jordi Duran as first author, the scientists show that in LD the accumulation of glycogen directly causes neuronal death and triggers cell imbalances such a decrease in autophagy and synaptic failure. All these alterations lead to the symptoms of LD, such as epilepsy.
Glycogen, a Trojan horse for neurons?
There was still a greater mystery to be solved. Was glycogen synthase truly a Trojan horse for neurons, as apparently established in the article in Nature Neuroscience? That is to say, was the accumulation of glycogen always fatal for cells, thus explaining why their glycogen synthesis machinery is silenced? The inevitable question was then why these cells had such machinery.
In another paper published in Journal of Cerebral Blood Flow & Metabolism, part of the Nature Group, the researchers provided the first evidence that neurons constantly store glycogen but in a different way: accumulating small amounts and using it as quickly as it becomes available. In this regard, the scientists set up new, more sensitive, analytical techniques to confirm that the machinery responsible for glycogen synthesis and degradation existed. In summary, they showed that, in small amounts, glycogen is beneficial for neurons.
“For example, while the liver accumulates glycogen in large amounts and releases it slowly to maintain blood sugar levels, above all when we sleep, neurons synthesize and degrade small amounts of this polysaccharide continuously. They do not use it as an energy store but as a rapid and small, but constant, source of energy,” explains Guinovart, also senior professor at the University of Barcelona (UB).
To observe the action of glycogen, the scientists forced cultured mouse neurons to survive under oxygen depletion. They demonstrated that the first cells to die were those in which the capacity to synthesise glycogen had been removed. The same experiments were performed in collaboration with Marco Milán’s “Development and growth control” group in the in vivo model of the fruit fly Drosophila melanogaster. These tests led to the same conclusions.
The researchers postulated that glycogen is a lifeguard under oxygen depletion, a condition that leads the brains to shut down and that often occurs at birth and in cerebral infarctions in adults, which leads to severe consequences, such a cerebral paralysis.
“It is the first function of glycogen that we have discovered in neurons, but we still have to identify its function in normal conditions and establish how the mechanism works,” says Jordi Duran. Postdoctoral researcher Isabel Saez is the first author of the article out today, which involved the collaboration of ICREA Research Professor Marco Milán’s lab.
The beneficial and toxic roles of brain glycogen are currently the focus of main research lines conducted by Joan Guinovart’s lab.
After death, twin brains show similar patterns of neuropathologic changes
Despite widespread use of a single term, Alzheimer’s disease is actually a diverse collection of diseases, symptoms and pathological changes. What’s happening in the brain often varies widely from patient to patient, and a trigger for one person may be harmless is another.
In a unique study, an international team of researchers led by USC psychologist Margaret Gatz compared the brains of twins where one or both died of Alzheimer’s disease. They found that many of the twin pairs not only had similar progressions of Alzheimer’s disease and dementia prior to death, but they also had similar combinations of pathologies — two-or-more unconnected areas of damage to the brain.
The paper is part of Gatz’s landmark body of work on aging and cognition with the Swedish Twin Registry, a large cohort study of more than 14,000 Swedish twins, now over the age of 65. Across nearly 30 years, Gatz’s work with twins — including genetically identical pairs — has shifted the study of Alzheimer’s disease to include the entire lifespan, including the effects of developmental exposure, periodontal disease, mental health, obesity and diabetes on later-life Alzheimer’s risk.
The current paper provides more evidence that there may not be a single smoking-gun cause of Alzheimer’s, but rather a range of potential causes to which we may be susceptible largely depending on our genetics. It appears in the current issue of the journal Brain Pathology.
“We try to make inferences based on tests and diagnoses, but we have to assume that what we’re seeing is a manifestation of what’s going on in these twins’ brains,” said Gatz, professor of psychology, gerontology and preventive medicine in USC Dornsife College. “For this reason, we wanted to compare the brains of twins to ask whether identical twins’ brains are actually more identical?”
The researchers had the rare opportunity to directly autopsy the brains of seven pairs of twins who both died after being receiving diagnostic evaluations over many years, including a pair of identical twins who were both diagnosed with Alzheimer’s and died within a year of one another at the age of 98.
“There may be risk factors that start to accumulate but don’t lead to a clinical diagnosis,” explained lead author Diego Iacono of the Karolinska Institute in Sweden and the Biomedical Research Institute. “We found that the presence of Alzheimer’s disease doesn’t preclude the presence of other damage. Looking at co-pathologies in twin pairs may present new areas for research aside from the typical factors.”
For example, while there’s wide consensus among experts about the course of Alzheimer’s disease and the presence of amyloid plaques and tangles in the brain, what starts the process going is less clear, including the role of lesions, Lewy bodies and vascular or ventricle damage, more often associated with specific types of dementia such as Parkinson’s disease.
“Identical twins tended to have similar combinations of pathologies. We looked not just at the hallmark indicators of Alzheimer’s, but at all the other damage in the brain. Across the whole array of neuropathological changes, the identical twins appeared to have more similar pathologies,” Gatz said. “This is fascinating: it’s not just a key pathology related to the twins’ diagnoses but the combination of things happening in their brains. We’re going to keep looking for what these combinations are.”
(Image: Getty)
Researchers generate new neurons in brains, spinal cords of living adult mammals
UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.
Although the research indicates it may someday be possible to regenerate neurons from the body’s own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer’s disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.
Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.
Scientists in UT Southwestern’s Department of Molecular Biology first successfully turned astrocytes – the most common non-neuronal brain cells – into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.
“Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons,” said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies.
“Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration,” Dr. Zhang explained. “Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming.”
The scientists’ two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.
In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.
The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.
In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added.
Because tumor growth is a concern when cells are reprogrammed to an earlier stage of development, the researchers followed the mice in the Nature Cell Biology study for nearly a year to look for signs of tumor formation and reported finding none.
(Image: Shutterstock)
Study in Fruitflies Strengthens Connection Among Protein Misfolding, Sleep Loss, and Age
Pulling an “all-nighter” before a big test is practically a rite of passage in college. Usually, it’s no problem: You stay up all night, take the test, and then crash, rapidly catching up on lost sleep. But as we age, sleep patterns change, and our ability to recoup lost sleep diminishes.
Researchers at the Perelman School of Medicine, University of Pennsylvania, have been studying the molecular mechanisms underpinning sleep. Now they report that the pathways of aging and sleep intersect at the circuitry of a cellular stress response pathway, and that by tinkering with those connections, it may be possible to alter sleep patterns in the aged for the better – at least in fruit flies.
Nirinjini Naidoo, PhD, associate professor in the Center for Sleep and Circadian Neurobiology and the Division of Sleep Medicine, led the study with postdoctoral fellow Marishka Brown, PhD, which was published online before print in the journal Neurobiology of Aging.
Increasing age is well known to disrupt sleep patterns in all sorts of ways. Elderly people sleep at night less than their younger counterparts and also sleep less well. Older individuals also tend to nap more during the day. Naidoo’s lab previously reported that aging is associated with increasing levels of protein unfolding, a hallmark of cellular stress called the “unfolded protein response.”
Protein misfolding is also a characteristic of several age-related neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, and as it turns out, also associated with sleep deprivation. Naidoo and her team wanted to know if rescuing proper protein folding behavior might counter some of the detrimental sleep patterns in elderly individuals.
Using a video monitoring system to compare the sleep habits of “young” (9–12 days old) and “aged” (8 weeks old) fruit flies, they found that aged flies took longer to recover from sleep deprivation, slept less overall, and had their sleep more frequently interrupted compared to younger control animals. However, adding a molecule that promotes proper protein folding – a molecular “chaperone” called PBA — mitigated many of those effects, effectively giving the flies a more youthful sleep pattern. PBA (sodium 4-phenylbutyrate) is a compound currently used to treat such protein-misfolding-based diseases as Parkinson’s and cystic fibrosis.
The team also asked the converse question: Can protein misfolding induce altered sleep patterns in young animals. Another drug, tunicamycin, induces protein misfolding and stress, and when the team fed it to young flies, their sleep patterns shifted towards those of aged flies, with less sleep overall, more interrupted sleep at night, and longer recovery from sleep deprivation.
Molecular analysis of sleep-deprived and PBA-treated flies suggested that PBA acts through the unfolded protein response. PBA, Naidoo says, had two effects on aged flies: it “consolidated” baseline sleep, increasing the total amount of time slept and shifted recovery sleep, after sleep deprivation, to look more like that of a young fly.
“It rescued the sleep patterns in the older flies,” she explains.
These results, Naidoo says, suggest three key messages. First, sleep loss leads to protein misfolding and cellular stress, and as we age, our ability to recover from that stress decreases. Second, aging and sleep apparently form a kind of negative “chicken-and-egg” feedback loop, in which sleep loss or sleep fragmentation lead to cellular stress, followed by neuronal dysfunction, and finally even poorer-quality sleep.
Sleep recharges neuronal batteries, Naidoo explains, and if a person is forced to stay awake, those batteries run down. Dwindling physiological resources must be devoted to the most critical cell functions, which do not necessarily include protein homeostasis. “Staying awake has a cost, and one of those costs is problems with protein folding.”
Finally, and most importantly, she says these results suggest — assuming they can be replicated in mice and humans – that it may be possible using drugs such as PBA to “fix sleep” in aged or mutant animals.
“People know that sleep deteriorates with aging,” Naidoo says, “But this might be able to be stopped or reversed with molecular chaperones.” Her team is now looking to determine if a similar situation exists in mammals and if better sleep translates into longer lifespan.
(Source: uphs.upenn.edu)
Geneticists Show How Molecular Switches Coordinate the Nervous System
Geneticists from Trinity College Dublin interested in ‘reverse engineering’ the nervous system have made an important discovery with wider implications for repairing missing or broken links. They found that the same molecular switches that induce originally non-descript cells to specialise into the billions of unique nerve cell types are also responsible for making these nerve cells respond differently to the environment.
The geneticists are beginning to understand how these molecular switches, called ‘transcription factors’, turn on specific cellular labels to form complex bundles of nerves. These bundles function to ensure we respond and react appropriately to the incredible amount of information our brains encounter. Understanding how to precisely program nerve cells could help to target missing or broken links following serious injury or the onset of degenerative diseases such as Alzheimer’s or Parkinson’s.
Commenting on the importance and wider implications of this discovery, Assistant Professor in Genetics at Trinity, Juan Pablo Labrador said: “We know very little of how individual nerve cells are programmed to assemble into specific nerves in living organisms to make specific circuits, so our work is like reverse engineering the nervous system.”
“To restore damaged or missing connections in the nervous system – for example, after spinal cord injuries or degenerative diseases such as Alzheimer’s or Parkinson’s – we need to know how nerve cells are programmed to make those connections in the first place. For that we require a complex ‘builder’s manual’ that tells us how to program the neurons to make the connections. What we are doing in my lab is trying to write this manual.”
The nervous system can be thought of as an incredibly complex network of wires, which are all arranged into different, related bundles to coordinate complex tasks. The wires are the cellular extensions from the individual nerve cells that assemble into bundles to form specific nerves. The geneticists have begun to understand how varied combinations of transcription factors work to generate different nerve cells and direct their wiring to form specific nerves.
By studying the behaviour of individual nerve cells that make connections with muscles, the geneticists discovered specific ‘footprints’ of labels that induced these nerve cells to assemble into specific bundles that link to their target muscles. Individual transcription factors are only able to turn on specific labels to some extent. It is only the action of all of them together that programmes the nerve cells to turn on all the labels required.
The research was just published in the high-profile journal Neuron. The team led by Assistant Professor Juan Pablo Labrador, found that the actions of the transcription factor influencing nerve cell differentiation in flies (‘Eve’) controls nerve cell surface labels.
The team also showed that if these labels, targeted by Eve, are expressed erroneously, the nerve cells will not form the correct nerves. Additionally, the team discovered that different combinations of transcription factors including Eve work as codes for different groups of labels that guide individual nerve development.
(Source: tcd.ie)
Scientists identify new Huntington disease pathway
An international group of researchers has identified a major new pathway thought to be involved in the development of Huntington disease. The findings, published in the Proceedings of the National Academy of Sciences journal, could eventually lead to new treatments for the disease, which currently has no cure.
Scientists at the BC Cancer Agency Research Centre and the Centre for Molecular Medicine and Therapeutics in Vancouver, Canada, and the MRC Toxicology Unit in Leicester, UK, studied mice and human tissue and found that the HACE1 gene is essential for mopping up toxic molecules during periods of oxidative stress, where harmful ‘reactive oxygen species’ build up in the cell.
Oxidative stress is thought to be involved in the development of a number of diseases including cancer and neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. Therefore finding out how this process occurs in the body is important for understanding the course of disease.
The body has evolved highly effective defence mechanisms that sense and respond to oxidative stress to protect the cells from damage. One of these protective mechanisms is controlled by a molecule called NRF2 which springs into action and switches on the production of proteins and enzymes that detoxify the cell.
In this study, scientists found that the HACE1 also plays a vital role in this detoxification process, by activating NRF2. The authors believe that this mechanism goes wrong in Huntington’s disease, leading to gradual destruction of nerve cells in the brain.
Lead author Dr Barak Rotblat, of the MRC Toxicology Unit, said:
“One of the early observations was that enhanced HACE1 expression rescued cells from mutant Huntingtin (the mutant protein that is responsible for Huntington disease) toxicity. We knew then that we had to figure out how HACE1 can protect these cells.
“Our evidence points towards a previously unknown role of HACE1 in Huntington disease and possibly other forms of neurodegeneration. It’s very early days, but if we were able to find a way to boost this pathway, we might be able to develop a treatment that halts, or even reverses progression of Huntington disease.”
HACE1 is already known to play a protective role against tumour formation, but its role in neurodegeneration has not been investigated before.
Dr Poul Sorensen, the senior author of the work from the BC Cancer Agency Research Centre and a Professor at the University of British Columbia, said:
“This is a glowing example of how work in one field, namely childhood cancers, where we first identified the HACE1 gene, has applications to a completely different disease, Huntington disease”.
In this study, researchers looked at mice with and without the HACE1 gene and found that those without the gene had more oxidative stress in the brain, and their response to this was impaired. Depleting HACE1 in cells also resulted in reduced NRF2 activity, leading to lower tolerance against oxidative stress triggers.
The scientists also looked at human brain samples from Huntington disease patients and found a striking reduction of HACE1 levels in the striatum – the area of the brain where the disease develops and is most damaged.
Finally, they looked at HACE1 in a cellular model of Huntington disease. They found that upping expression of the gene in nerve precursor cells protected them against oxidative stress.
(Source: mrc.ac.uk)
New blood cells fight brain inflammation
Hyperactivity of our immune system can cause a state of chronic inflammation. If chronic, the inflammation will affect our body and result in disease. In the devastating disease multiple sclerosis, hyperactivity of immune cells called T-cells induce chronic inflammation and degeneration of the brain. Researchers at BRIC, the University of Copenhagen, have identified a new type of regulatory blood cells that can combat such hyperactive T-cells in blood from patients with multiple sclerosis. By stimulating the regulatory blood cells, the researchers significantly decreased the level of brain inflammation and disease in a biological model. The results are published in the journal Nature Medicine.
Molecule activate anti-inflammatory blood cells
The new blood cells belong to the group of our white blood cells called lymphocytes. The cells express a molecule called FoxA1 that the researchers found is responsible for the cells’ development and suppressive functions.
"We knew that some unidentified blood cells were able to inhibit multiple sclerosis-like disease in mice and through gene analysis we found out, that these cells are a subset of our lymphocytes expressing the gene FoxA1. Importantly, when inserting FoxA1 into normal lymphocytes with gene therapy, we could change them to actively regulate inflammation and inhibit multiple sclerosis", explains associated professor Yawei Liu leading the experimental studies.
Image caption: Tissue sections from an untreated diseased brain and a FoxA1-treated brain from the researchers biological model. (Photo: Yawei Liu)
Activating own blood cells for treatment of disease
FoxA1 expressing lymphocytes were not known until now, and this is the first documentation of their importance in controlling multiple sclerosis. The number of people living with this devastating disease around the world has increased by 10 percent in the past five years to 2.3 million. It affects women twice more than men and no curing treatment exists. The research group headed by professor Shohreh Issazadeh-Navikas from BRIC examined blood of patients with multiple sclerosis, before and after two years of treatment with the drug interferon-beta. They found that patients who benefit from the treatment increase the number of this new blood cell type, which fight disease.
Image caption: FoxA1-lymphocytes. (Photo: Yawei Liu)
“From a therapeutic viewpoint, our findings are really interesting and we hope that they can help finding new treatment options for patients not benefiting from existing drugs, especially more chronic and progressive multiple sclerosis patients. In our model, we could activate lymphocytes by chemical stimulation and gene therapy, and we are curios whether this can be a new treatment strategy”, says professor Shohreh Issazadeh-Navikas.
And this is exactly what the research group will focus on at next stage of their research. They have already started to test whether the new FoxA1-lymphocytes can prevent degradation of the nerve cell’s myelin layer and brain degeneration in a model of progressive multiple sclerosis. Besides multiple sclerosis, knowledge on how to prevent chronic inflammation will also be valuable for other autoimmune diseases like type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis, where inflammation is a major cause of the disease.
(Source: news.ku.dk)
Finding could explain age-related decline in motor function
Scientists from the School of Medicine at The University of Texas Health Science Center at San Antonio have found a clue as to why muscles weaken with age. In a study published today in The Journal of Neuroscience, they report the first evidence that “set points” in the nervous system are not inalterably determined during development but instead can be reset with age. They observed a change in set point that resulted in significantly diminished motor function in aging fruit flies.
“The body has a set point for temperature (98.6 degrees), a set point for salt level in the blood, and other homeostatic (steady-state) set points that are important for maintaining stable functions throughout life,” said study senior author Ben Eaton, Ph.D., assistant professor of physiology at the Health Science Center. “Evidence also points to the existence of set points in the nervous system, but it has never been observed that they change, until now.”
Dr. Eaton and lead author Rebekah Mahoney, a graduate student, recorded changes in the neuromuscular junction synapses of aging fruit flies. These synapses are spaces where neurons exchange electrical signals to enable motor functions such as walking and smiling. “We observed a change in the synapse, indicating that the homeostatic mechanism had adjusted to maintain a new set point in the older animal,” Mahoney said.
The change was nearly 200 percent, and the researchers predicted that it would leave muscles more vulnerable to exhaustion.
Aside from impairing movement in aging animals, a new functional set point in neuromuscular junctions could put the synapse at risk for developing neurodegeneration — the hallmark of disorders such as Alzheimer’s and Parkinson’s diseases, Mahoney said.
“Observing a change in the set point in synapses alters our paradigms about how we think age affects the function of the nervous system,” she said.
It appears that a similar change could lead to effects on learning and memory in old age. An understanding of this phenomenon would be invaluable and could lead to development of novel therapies for those issues, as well.
(Source: uthscsa.edu)