Posts tagged brain cells
Articles and news from the latest research reports.
Neurons Get Their Neighbors To Take Out Their Trash
Biologists have long considered cells to function like self-cleaning ovens, chewing up and recycling their own worn out parts as needed. But a new study challenges that basic principle, showing that some nerve cells found in the eye pass off their old energy-producing factories to neighboring support cells to be “eaten.” The find, which may bear on the roots of glaucoma, also has implications for Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS) and other diseases that involve a buildup of “garbage” in brain cells.
The study was led by Nicholas Marsh-Armstrong, Ph.D., a research scientist at the Kennedy Krieger Institute and an associate professor in the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, together with Mark H. Ellisman, Ph.D., a neuroscience professor at the University of California, San Diego. In a previous study, the two had seen hints that retinal ganglion cells, which transmit visual information from the eye to the brain, might be handing off bits of themselves to astrocytes, cells that surround and support the eye’s signal-transmitting neurons. They appeared to pass them to astrocytes at the optic nerve head, the beginning of the long tendril that connects retinal ganglion cells from the eye to the brain. Specifically, they suspected that the neuronal bits being passed on were mitochondria, which are known as the powerhouses of the cell.
To find out whether this was really the case, Marsh-Armstrong’s research group genetically modified mice so that they produced indicators that glowed in the presence of chewed up mitochondria. Ellisman’s group then used cutting-edge electron microscopy to reconstruct 3-D images of what was happening at the optic nerve head. The researchers saw that astrocytes were, indeed, breaking down large numbers of mitochondria from neighboring retinal ganglion cells.
“This was a very surprising study for us, because the findings go against the common understanding that each cell takes care of its own trash,” says Marsh-Armstrong. It is particularly interesting that the newly discovered process occurs at the optic nerve head, he notes, as that is the site thought to be at fault in glaucoma. He plans to investigate whether the mitochondria disposal process is relevant to this disease, the second leading cause of blindness worldwide.
But the implications of the results go beyond the optic nerve head, Marsh-Armstrong says, as a buildup of “garbage” inside cells causes neurodegenerative diseases such as Parkinson’s, Alzheimer’s and ALS. “By showing that this type of alternative disposal happens, we’ve opened up the door for others to investigate whether similar processes might be happening with other cell types and cellular parts other than mitochondria,” he says.
Scientists take totally tubular journey through brain cells
In a new study, scientists at the National Institutes of Health took a molecular-level journey into microtubules, the hollow cylinders inside brain cells that act as skeletons and internal highways. They watched how a protein called tubulin acetyltransferase (TAT) labels the inside of microtubules. The results, published in Cell, answer long-standing questions about how TAT tagging works and offer clues as to why it is important for brain health.
(Image caption: NIH scientists watched the inside of brain cell tubes, called microtubules, get tagged by a protein called TAT. Tagging is a critical process in the health and development of nerve cells. Credit: Courtesy of the Roll-Mecak lab, NINDS, Bethesda, MD)
Microtubules are constantly tagged by proteins in the cell to designate them for specialized functions, in the same way that roads are labeled for fast or slow traffic or for maintenance. TAT coats specific locations inside the microtubules with a chemical called an acetyl group. How the various labels are added to the cellular microtubule network remains a mystery. Recent findings suggested that problems with tagging microtubules may lead to some forms of cancer and nervous system disorders, including Alzheimer’s disease, and have been linked to a rare blinding disorder and Joubert Syndrome, an uncommon brain development disorder.
“This is the first time anyone has been able to peer inside microtubules and catch TAT in action,” said Antonina Roll-Mecak, Ph.D., an investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and the leader of the study.
Microtubules are found in all of the body’s cells. They are assembled like building blocks, using a protein called tubulin. Microtubules are constructed first by aligning tubulin building blocks into long strings. Then the strings align themselves side by side to form a sheet. Eventually the sheet grows wide enough that it closes up into a cylinder. TAT then bonds an acetyl group to alpha tubulin, a subunit of the tubulin protein.
Some microtubules are short-lived and can rapidly change lengths by adding or removing tubulin pieces along one end, whereas others remain unchanged for longer times. Recognizing the difference may help cells function properly. For example, cells may send cargo along stable microtubules and avoid ones that are being rebuilt. Cells appear to use a variety of chemical labels to describe the stability of microtubules.
“Our study uncovers how TAT may help cells distinguish between stable microtubules and ones that are under construction,” said Dr. Roll-Mecak. According to Dr. Roll-Mecak, high levels of microtubule tagging are unique to nerve cells and may be the reason that they have complex shapes allowing them to make elaborate connections in the brain.
For decades scientists knew that the insides of long-lived microtubules were often tagged with acetyl groups by TAT. Changes in acetylation may influence the health of nerve cells. Some studies have shown that blocking this form of microtubule tagging leads to nerve defects, brain abnormalities or degeneration of nerve fibers. Since the discovery of microtubule acetylation, scientists have been puzzled about how TAT accesses the inside of the microtubules and how the tagging reaction happens.
To watch TAT at work, Dr. Roll-Mecak and her colleagues took high resolution movies of individual TAT molecules interacting with microtubules in real time. They saw that TAT surfs through the inside of microtubules and although it can find acetylation sites quickly, the process of adding the tag occurs very slowly.
In general, tagging reactions work like keys fitting into locks: the better the key fits, the faster the lock can open. Similarly, the rate of the reactions is determined by how well TAT molecules fit around tagging sites.
Dr. Roll-Mecak’s team investigated this idea by using a technique called X-ray crystallography to look at how atoms on TAT molecules interact with acetylation sites on tubulin molecules. Their results suggested that TAT fit poorly around the sites.
“It looks as though TAT can easily journey through microtubules spotting acetylation sites but may only label those that are stable for longer periods of time,” said Dr. Roll-Mecak.
This may help cells identify the microtubules they need to rapidly change shapes or send cargo to other places. Further studies may help researchers understand how microtubule tagging influences nerve cells in health and disease.
(Source: ninds.nih.gov)
Unlocking the potential of stem cells to repair brain damage
A QUT scientist is hoping to unlock the potential of stem cells as a way of repairing neural damage to the brain.
Rachel Okolicsanyi, from the Genomics Research Centre at QUT’s Institute of Health and Biomedical Innovation, said unlike other cells in the body which were able to divide and replicate, once most types of brain cells died, the damage was deemed irreversible.
Ms Okolicsanyi is manipulating adult stem cells from bone marrow to produce a population of cells that can be used to treat brain damage.
"My research is a step in proving that stem cells taken from the bone marrow can be manipulated into neural cells, or precursor cells that have the potential to replace, repair or treat brain damage," she said.
Ms Okolicsanyi’s research has been published in Developmental Biology journal, and outlines the potential stem cells have for brain damage repair.
"What I am looking at is whether or not stem cells from the bone marrow have the potential to differentiate or mature into neural cells," she said.
"Neural cells are those cells from the brain that make everything from the structure of the brain itself, to all the connections that make movement, voice, hearing and sight possible."
Ms Okolicsanyi’s research is looking at heparin sulfate proteoglycans - a family of proteins found on the surface of all cells.
"What we are hoping is that by manipulating this particular family of proteins we can encourage the stem cells to show a higher percentage of neural markers indicating that they could mature into neural cells rather than what they would normally do, which is form into bone, cartilage and fat," she said.
"We will manipulate these cells by modifying the surrounding environment. For example we will add chemicals such as complex salts and other commonly found biological chemicals to feed these cells and this will either inhibit or encourage cellular processes."
Ms Okolicsanyi said by doing this, it would be possible to see the different reactions stem cells had to particular chemicals and find out whether these chemicals could increase or decrease the neural markers in the cells.
"The proteins that we are interested in are almost like a tree," she said.
"They have a core protein that is attached to the cell surface and they have these heparin sulfate chains that branch off.
"So when the chemicals we add influence the stem cell in different ways, it will help us understand the interactions between proteins and the resulting changes in the cell.
"In the short-term it is proof that simple manipulations can influence the stem cell and in the long-term it is about the possibility of increasing the neural potential of these stem cells."
Ms Okolicsanyi said the big picture plan was to be able to introduce stem cells into the brain that would be able to be manipulated to repair damaged brain cells.
"The idea, for example, is that in stroke patients where the patient loses movement, speech or control of one side of their face because the brain’s electrical current is impaired, that these stem cells will be able to be introduced and help the electrical current reconnect by bypassing the damaged cells."
(Image: Fotolia)
Learning Early in Life May Help Keep Brain Cells Alive
Using your brain – particularly during adolescence – may help brain cells survive and could impact how the brain functions after puberty.
According to a recently published study in Frontiers in Neuroscience, Rutgers behavioral and systems neuroscientist Tracey Shors, who co-authored the study, found that the newborn brain cells in young rats that were successful at learning survived while the same brain cells in animals that didn’t master the task died quickly.
“In those that didn’t learn, three weeks after the new brain cells were made, nearly one-half of them were no longer there,” said Shors, professor in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers. “But in those that learned, it was hard to count. There were so many that were still alive.”
The study is important, Shors says, because it suggests that the massive proliferation of new brain cells most likely helps young animals leave the protectiveness of their mothers and face dangers, challenges and opportunities of adulthood.
Scientists have known for years that the neurons in adult rats, which are significant but fewer in numbers than during puberty, could be saved with learning, but they did not know if this would be the case for young rats that produce two to four times more neurons than adult animals.
By examining the hippocampus – a portion of the brain associated with the process of learning – after the rats learned to associate a sound with a motor response, scientists found that the new brain cells injected with dye a few weeks earlier were still alive in those that had learned the task while the cells in those who had failed did not survive.
“It’s not that learning makes more cells,” says Shors. “It’s that the process of learning keeps new cells alive that are already present at the time of the learning experience.”
Since the process of producing new brain cells on a cellular level is similar in animals, including humans, Shors says ensuring that adolescent children learn at optimal levels is critical.
“What it has shown me, especially as an educator, is how difficult it is to achieve optimal learning for our students. You don’t want the material to be too easy to learn and yet still have it too difficult where the student doesn’t learn and gives up,” Shors says.
So, what does this mean for the 12-year-old adolescent boy or girl?
While scientists can’t measure individual brain cells in humans, Shors says this study, on the cellular level, provides a look at what is happening in the adolescent brain and provides a window into the amazing ability the brain has to reorganize itself and form new neural connections at such a transformational time in our lives.
“Adolescents are trying to figure out who they are now, who they want to be when they grow up and are at school in a learning environment all day long,” says Shors. “The brain has to have a lot of strength to respond to all those experiences.”
New epilepsy treatment offers ‘on demand’ seizure suppression
A new treatment for drug-resistant epilepsy with the potential to suppress seizures ‘on demand’ with a pill, similar to how you might take painkillers when you feel a headache coming on, has been developed by UCL researchers funded by the Wellcome Trust.
The treatment, described in Nature Communications, combines genetic and chemical approaches to suppress seizures without disrupting normal brain function. The technique was demonstrated in rodents but in future we could see people controlling seizures on-demand with a simple pill.
Epilepsy affects around 50 million people worldwide including 600,000 in the UK and around a quarter of cases are resistant to conventional treatments. Many of these cases could be addressed by the new treatment method, which relies on genetic modification of brain cells to make them sensitive to a normally inactive compound.
“First, we inject a modified virus into the area of the brain where seizures arise,” explains Professor Dimitri Kullmann of the UCL Institute of Neurology, senior author of the research. “This virus instructs the brain cells to make a protein that is activated by CNO (clozapine-N-oxide), a compound that can be taken as a pill. The activated protein then suppresses the over-excitable brain cells that trigger seizures, but only in the presence of CNO.
“At the moment, severe seizures are treated with drugs that suppress the excitability of all brain cells, and patients therefore experience side effects. Sometimes the dose required to stop seizures is so high that patients need to be sedated and taken to intensive care. If we can take our new method into the clinic, which we hope to do within the next decade, we could treat patients who are susceptible to severe seizures with a one-off injection of the modified virus, and then use CNO only when needed.
“CNO would be given as a pill in the event that patients could predict when seizures were likely to occur. For example, many people with treatment-resistant epilepsy experience clusters of seizures, where severe seizures are preceded by smaller ones. Seizure risk is also high when people are ill, sleep deprived, or at certain times of the menstrual cycle, so these would all be good times to take the pill as a preventative measure. In urgent situations, the compound could be given as an injection. We could even consider a fully automatic delivery system, where CNO was given by a pump, as is done for insulin in some people with diabetes.”
As CNO has a half-life of about a few hours and only affects the pre-treated epileptic parts of the brain, the new method avoids the need to permanently alter the brain or treat the whole brain with seizure-suppressing drugs. It builds on similar work by Professor Kullmann’s group using gene therapy to ‘calm down’ brain cells, or using light pulses to activate seizure-suppressing receptors in the brain. The new technique works in a similar way but is reversible and avoids the need for invasive devices to deliver light to the brain.
“After the one-off injection into affected areas of the brain, our new technique would require nothing beyond CNO, administered as an injection or a pill, to suppress seizures when required,” says Professor Kullmann. “This makes it more attractive than alternative forms of targeted therapy such as surgery to remove the brain region where seizures arise, or gene therapy that permanently alters the excitability of brain cells.
“Although there is currently no evidence that permanently suppressing excitability in a small area affects brain function, we cannot be sure that it would have no impact long-term. Our new method is completely reversible, so if there were any side-effects then people could simply stop taking the CNO pill.”
(Source: ucl.ac.uk)
Novel Protein Fragments May Protect Against Alzheimer’s
The devastating loss of memory and consciousness in Alzheimer’s disease is caused by plaque accumulations and tangles in neurons, which kill brain cells. Alzheimer’s research has centered on trying to understand the pathology as well as the potential protective or regenerative properties of brain cells as an avenue for treating the widespread disease.
Now Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University’s Sagol School of Neuroscience, has discovered novel protein fragments that have proven protective properties for cognitive functioning.
In a study published in the Journal of Alzheimer’s Disease, Prof. Gozes examined the protective effects of two newly discovered protein fragments in mice afflicted with Alzheimer’s disease-like symptoms. Her findings have the potential to serve as a pipeline for new drug candidates to treat the disease.
NAP time for Alzheimer’s
"Several years ago we discovered that NAP, a snippet of a protein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s," said Prof. Gozes. "Now, we’re investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery."
Prof. Gozes’ research focused on the microtubule network, a crucial part of cells in our bodies. Microtubules act as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s, this network breaks down, hindering motor abilities and cognitive function.
"NAP operates through the stabilization of microtubules — tubes within the cell which maintain cellular shape. They serve as ‘train tracks’ for movement of biological material," said Prof. Gozes. "This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer’s disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."
Down the tubes
In her new study, Prof. Gozes and her team looked at the subunit of the microtubule — the tubulin — and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer’s; increased tangle accumulation is indicative of cognitive deterioration. Prof. Gozes decided to test both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, she tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients’ brains.
"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline," said Prof. Gozes. "We tested one compound — a tubulin fragment — and saw that it protected against cognitive deficits. When we looked at the ‘dementia’-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."
Prof. Gozes and her team also measured the brain-to-body mass ratio, an indicator of brain degeneration, and saw a significant decrease in the mouse model compared to normal mice. Following the introduction of the tubulin fragments, however, the mouse’s brain to body ratio returned to normal. “We clearly see here the protective effect of the treatment,” said Prof. Gozes. “We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models.”
(Image: Getty Images)
Mouse study offers new clues to cognitive decline
New research suggests that certain types of brain cells may be “picky eaters,” seeming to prefer one specific energy source over others. The finding has implications for understanding the cognitive decline seen in aging and degenerative diseases such as Alzheimer’s and multiple sclerosis.
(Image caption: Neural stem cells differentiate into three different cell types: neurons (purple), oligodendrocytes (red), which produce axon insulation, and astrocytes (green), which also support neurons. Cell nuclei are shown in blue. Credit: Liana Roberts Stein)
Studying mice, investigators from Washington University School of Medicine in St. Louis showed that a specific energy source called NAD is important in cells responsible for maintaining the overall structure of the brain and for performing complex cognitive functions. NAD (nicotinamide adenine dinucleotide) is a molecule that harvests energy from nutrients in food and converts it into a form cells can use.
The work appears in two journal articles — in the May 8 issue of The EMBO Journal, a publication of the European Molecular Biology Organization, and in a recent issue of The Journal of Neuroscience.
“We are interested in understanding how cells make NAD and what implications that has for cellular function, especially in the context of aging and longevity,” said Shin-ichiro Imai, MD, PhD, professor of developmental biology and of medicine and senior author of both papers. “We know, for example, NAD levels decrease with age in tissues such as muscle and fat. We wanted to find out if the same is true in the brain.”
The investigators looked at two types of brain cells: adult neural stem cells, responsible for maintaining supplies of neurons and their supporting cells, and forebrain neurons, vital for performing complex cognitive tasks.
In The EMBO Journal, they reported that NAD levels decreased with age in the mouse hippocampus, a vital region of the brain for cognition. The researchers then used genetic techniques to find out what would happen when NAD manufacturing is turned off in the adult neural stem cells of the mouse brain.
“Neural stem cells are very metabolically expensive, so you might expect them to be particularly vulnerable to loss of an energy source,” said first author Liana Roberts Stein, PhD, postdoctoral researcher in Imai’s lab. “There are other energy sources for brain cells, such as glucose, but no one had ever looked at where NAD is coming from in these cells.”
According to the researchers, there are four pathways of NAD synthesis, and the scientists focused on just one. They wanted to find out whether this particular pathway — a longtime focus of Imai’s lab — is important for these cells or if the other routes could compensate.
The pathway begins with the B vitamin nicotinamide. Cells take dietary nicotinamide and, with a helper protein called Nampt, manufacture a molecule called NMN, which then is processed further to make NAD. When Stein eliminated Nampt from neural stem cells, several significant changes took place.
Levels of NAD dropped, and the neural stem cells stopped dividing; they stopped renewing themselves; and they stopped being able to create important cells that insulate axons, the “wires” that carry electrical signals throughout the brain. With less insulation, these signals slow down, impairing brain function.
Imai and Stein pointed out possible therapeutic implications of this finding, especially in light of what is known about cognitive decline in aging and certain diseases.
“Scientists have shown that with age there actually isn’t a large decrease in the total neuron population,” Stein said. “But there is quite a substantial decrease in white matter, which is primarily composed of cells that function in axon insulation. This pathway also could be relevant in conditions involving loss of cells that make this insulation, like multiple sclerosis.”
Imai and Stein also found they could prevent the loss of the neural stem cells missing Nampt by giving the mice NMN, the next molecule in the chain of events leading to NAD.
“We gave the mice NMN in their drinking water for 12 months,” Stein said. “And at the higher dose, we saw a rescue of the neural stem cell pool in aged mice.”
Imai called this finding exciting because it supports the possibility of a future NMN supplement.
“We think that NMN could convey a similar effect in people,” Imai said. “A future clinical trial for NMN will tell us if it has any efficacy in humans.”
In addition to maintaining stem cell populations and keeping the brain supplied with all its cell types, the investigators showed that NAD also is vital for the process of cognition itself.
Reporting in The Journal of Neuroscience, they showed that neurons of the mouse forebrain depend heavily on NAD in normal cognitive function. Instead of deleting Nampt in stem cells, this time Stein deleted it only in neurons of the forebrain. All other cells were normal, including those that make axon insulation.
Without Nampt and its eventual product, NAD, in forebrain neurons, the behavior of the mice changed dramatically, according to the investigators.
“The mice were really hyperactive, with a twofold increase in activity levels,” Stein said. “They also showed a loss of anxiety-like behaviors. These mice didn’t seem to sense or fear potentially threatening situations and showed fairly drastic memory defects.”
Stein pointed out that these neurons are in a region of the brain known to be particularly vulnerable to neurodegenerative conditions from Alzheimer’s disease to stroke.
“It’s possible that these neurons’ dependence on Nampt is responsible for their extreme susceptibility to these conditions,” she said. “It would be interesting to model some of these diseases in mice and see if supplementing NMN provides any benefit to their behavior or memory.”
“We haven’t done that study yet,” Imai added. “But this is the direction the entire field is going.”
(Source: news.wustl.edu)
Stem cells from teeth can make brain-like cells
University of Adelaide researchers have discovered that stem cells taken from teeth can grow to resemble brain cells, suggesting they could one day be used in the brain as a therapy for stroke.
In the University’s Centre for Stem Cell Research, laboratory studies have shown that stem cells from teeth can develop and form complex networks of brain-like cells. Although these cells haven’t developed into fully fledged neurons, researchers believe it’s just a matter of time and the right conditions for it to happen.
"Stem cells from teeth have great potential to grow into new brain or nerve cells, and this could potentially assist with treatments of brain disorders, such as stroke," says Dr Kylie Ellis, Commercial Development Manager with the University’s commercial arm, Adelaide Research & Innovation (ARI).
Dr Ellis conducted this research as part of her Physiology PhD studies at the University, before making the step into commercialisation. The results of her work have been published in the journal Stem Cell Research & Therapy.
"The reality is, treatment options available to the thousands of stroke patients every year are limited," Dr Ellis says. "The primary drug treatment available must be administered within hours of a stroke and many people don’t have access within that timeframe, because they often can’t seek help for some time after the attack.
"Ultimately, we want to be able to use a patient’s own stem cells for tailor-made brain therapy that doesn’t have the host rejection issues commonly associated with cell-based therapies. Another advantage is that dental pulp stem cell therapy may provide a treatment option available months or even years after the stroke has occurred," she says.
Dr Ellis and her colleagues, Professors Simon Koblar, David O’Carroll and Stan Gronthos, have been working on a laboratory-based model for actual treatment in humans. As part of this research Dr Ellis found that stem cells derived from teeth developed into cells that closely resembled neurons.
"We can do this by providing an environment for the cells that is as close to a normal brain environment as possible, so that instead of becoming cells for teeth they become brain cells," Dr Ellis says.
"What we developed wasn’t identical to normal neurons, but the new cells shared very similar properties to neurons. They also formed complex networks and communicated through simple electrical activity, like you might see between cells in the developing brain."
This work with dental pulp stem cells opens up the potential for modelling many more common brain disorders in the laboratory, which could help in developing new treatments and techniques for patients.
Biologists discover a key regulator in the pacemakers of our brain and heart
Biologists have discovered how an outer shield over T-type channels change the electrochemical signaling of heart and brain cells. Understanding how these shields work will help researchers eventually develop a new class of drugs for treating epilepsy, cardiovascular disease and cancer.
The study from the University of Waterloo is published in the Journal of Biological Chemistry today and is featured as the “Paper of the Week” for its significance.
The researchers discovered T-type channels in the pond snail, Lymnaea stagnalis, can shift from using calcium ions to using sodium ions to generate the electrical signal because of an outer shield of amino acids called a turret situated above the channel’s entrance.
Low voltage T-type channels generate tiny pulses of current at regular intervals by selectively passing positively charged cations across the cell’s membrane through a gate-like channel. The channels are normally extremely selective, allowing just one sodium ion to pass for every 10,000 calcium ions.
The resulting rhythmic signals produced by this transfer of cations are what support the synchronous contraction of our heart muscles and neuronal firing in parts of the brain, like the thalamus, which helps regulate our sleep-wake cycle, or circadian rhythm.
In addition to their published findings, the researchers also found the shield-like turrets in pond snails restrict access of therapeutic drugs to the channel.
T-type channels in pond snails and other invertebrates are similar to those found in humans. Although pond snails reach only 7 cm in length, its simple neural network and physiology make it a popular model organism with neurobiologists.
Over-active T-type channels are linked to epilepsy, cardiac problems, neuropathic pain, as well as the spreading of several kinds of cancer. Drugs that could quench out-of-control T-type channel activity are unable to bind to the channels themselves.
“We wanted to understand the molecular structures of T-type channels,” said Spafford. “How they pass ionic currents to generate electrical activity, and to identify drug binding sites, and the drugs which may block these channels to treat neurological disease or heart complications.”
The group is currently investigating how dismantling this extracellular turret will improve drug access and binding in T-type channels.
On the Defensive
TAU discovers that protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells
People diagnosed with Huntington’s disease, most in their mid-thirties and forties, face a devastating prognosis: complete mental, physical, and behavioral decline within two decades. “Mutant” protein clusters, long blamed for the progression of the genetic disease, have been the primary focus of therapies in development by pharmaceutical companies. But according to new research from Prof. Gerardo Lederkremer and Dr. Julia Leitman of Tel Aviv University’s Department of Cell Research and Immunology, in collaboration with Prof. Ulrich Hartl of the Max Planck Institute for Biochemistry, these drugs may not only be ineffective — they may pose a serious threat to patients.
In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington’s disease. On the contrary, these aggregates actually serve as a defense mechanism for “stressed” brain cells. Conducted on tissue cultures using cutting-edge microscopic technology, their studies identified a different causative agent — the “stress response” of affected brain cells.
"The upsetting implication for therapy of this disease is that drugs being developed to interfere with the formation of protein aggregates may in fact be detrimental," said Prof. Lederkremer. "The identification of the new cause will hopefully lead to the development of new therapeutic approaches. This may hold true for other neurodegenerative diseases as well."
Starting from genetic scratch
Prof. Lederkremer and his team chose to examine the effect of protein aggregates in the pathology of Huntington’s disease because its genetic cause is well-known, unlike those of other neurodegenerative diseases, such as Parkinson’s, whose origins remain less clear.
"What we found in this study — a surprise, although we suspected it — was that damage to the cells, the cell ‘stress’ that leads to death of cells, appeared well before the protein aggregates did," said Prof. Lederkremer. "And even more surprising, when the aggregates finally appeared, the stress was reduced, in some cases even stopping. The actual process of forming an aggregate was protective, isolating and segregating the problematic proteins. This explains why in autopsies of people who died of Huntington’s and other diseases like Alzheimer’s or old age, the protein aggregates in the brains were all quite similar, reflecting no specific disease link."
By interfering with the stress response of brain cells, rather than the formation of protein clusters, scientists may be able to slow, or even halt, the progression of neurodegenerative diseases. According to Prof. Lederkremer, this research paves the way for a revolutionary new direction for pharmaceutical research to treat Huntington’s, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases.
Response to stress
"The practical consequences are that several companies are already in advanced stages of development of drugs inhibiting this form of protein aggregate, interfering with the body’s natural process to protect the brain," said Prof. Lederkremer. "But the drugs should be focused on another area altogether, and the protein aggregates, a protective resource for the brain, should be left intact."
Samples of brain cells from mouse models afflicted with Huntington’s disease were examined using “live cell imaging,” the study of live cells through time-lapse microscopy. Prof. Lederkremer and his team were thus able to identify a compound that modified brain cells’ response to stress, promoting their survival.
"Our approach was to interfere with the stress response instead of the formation of the protein aggregates, and the lab succeeded in identifying a compound that altered the response, rescuing affected cells from death," said Prof. Lederkremer. "Our findings are most encouraging for the development of a therapy for this devastating disease, which is presently incurable."
(Source: aftau.org)