Neuroscience

Most schools across the United States provide simple vision tests to their students—not to prescribe glasses, but to identify potential problems and recommend a trip to the optometrist. Researchers are now on the cusp of providing the same kind of service for autism.

Researchers at Duke University have developed software that tracks and records infants’ activity during videotaped autism screening tests. Their results show that the program is as good at spotting behavioral markers of autism as experts giving the test themselves, and better than non-expert medical clinicians and students in training.

The results appear online in the journal Autism Research and Treatment.

“We’re not trying to replace the experts,” said Jordan Hashemi, a graduate student in computer and electrical engineering at Duke. “We’re trying to transfer the knowledge of the relatively few autism experts available into classrooms and homes across the country. We want to give people tools they don’t currently have, because research has shown that early intervention can greatly impact the severity of the symptoms common in autism spectrum disorders.”

The study focused on three behavioral tests that can help identify autism in very young children.

In one test, an infant’s attention is drawn to a toy being shaken on the left side and then redirected to a toy being shaken on the right side. Clinicians count how long it takes for the child’s attention to shift in response to the changing stimulus. The second test passes a toy across the infant’s field of view and looks for any delay in the child tracking its motion. In the last test, a clinician rolls a ball to a child and looks for eye contact afterward—a sign of the child’s engagement with their play partner.

In all of the tests, the person administering them isn’t just controlling the stimulus, he or she is also counting how long it takes for the child to react—an imprecise science at best. The new program allows testers to forget about taking measurements while also providing more accuracy, recording reaction times down to tenths of a second.

“The great benefit of the video and software is for general practitioners who do not have the trained eye to look for subtle early warning signs of autism,” said Amy Esler, an assistant professor of pediatrics and autism researcher at the University of Minnesota, who participated in some of the trials highlighted in the paper.

“The software has the potential to automatically analyze a child’s eye gaze, walking patterns or motor behaviors for signs that are distinct from typical development,” Esler said. “These signs would signal to doctors that they need to refer a family to a specialist for a more detailed evaluation.”

According to Hashemi and his adviser, Guillermo Sapiro, professor of electrical and computer engineering and biomedical engineering at Duke, because the program is non-invasive, it could be useful immediately in homes and clinics. Neither, however, expects it to become widely used—not because clinicians, teachers and parents aren’t willing, but because the researchers are working on an even more practical solution.

Later this year, the Duke team (which includes students and faculty from engineering and psychiatry) plans to test a new tablet application that could do away with the need for a person to administer any tests at all. The program would watch for physical and facial responses to visual cues played on the screen, analyze the data and automatically report any potential red flags. Any parent, teacher or clinician would simply need to download the app and sit their child down in front of it for a few minutes.

The efforts are part of the Information Initiative at Duke, which connects researchers from disparate fields to experts in computer programming to help analyze large data sets.

“We’re currently working with autism experts at Duke Medicine to determine what sorts of easy tests could be used on just a computer or tablet screen to spot any potential concerns,” said Sapiro. “The goal is to mimic the same sorts of social interactions that the tests with the toys and balls measure, but without the toys and balls. The research has shown that the earlier autism can be spotted, the more beneficial intervention can be. And we want to provide everyone in the world with the ability to spot those signs as early as possible.”

A type of retina cell plays a more critical role in vision than previously known, a team led by Johns Hopkins University researchers has discovered.

Working with mice, the scientists found that the ipRGCs – an atypical type of photoreceptor in the retina – help detect contrast between light and dark, a crucial element in the formation of visual images. The key to the discovery is the fact that the cells express melanopsin, a type of photopigment that undergoes a chemical change when it absorbs light.

“We are quite excited that melanopsin signaling contributes to vision even in the presence of functional rods and cones,” postdoctoral fellow Tiffany M. Schmidt said.

Schmidt is lead author of a recently published study in the journal Neuron. The senior author is Samer Hattar, associate professor of biology in the university’s Krieger School of Arts and Sciences. Their findings have implications for future studies of blindness or impaired vision.

Rods and cones are the most well-known photoreceptors in the retina, activating in different light environments. Rods, of which there are about 120 million in the human eye, are highly sensitive to light and turn on in dim or low-light environments. Meanwhile the 6 million to 7 million cones in the eye are less sensitive to light; they drive vision in brighter light conditions and are essential for color detection.

Rods and cones were thought to be the only light-sensing photoreceptors in the retina until about a decade ago when scientists discovered a third type of retinal photoreceptor – the ipRGC, or intrinsically photosensitive retinal ganglion cell – that contains melanopsin. Those cells were thought to be needed exclusively for detecting light for non-image-dependent functions, for example, to control synchronization of our internal biological clocks to daytime and the constriction of our pupils in response to light.

“Rods and cones were thought to mediate vision and ipRGCs were thought to mediate these simple light-detecting functions that happen outside of conscious perception,” Schmidt said. “But our experiments revealed that ipRGCs influence a greater diversity of behaviors than was previously known and actually contribute to an important aspect of image-forming vision, namely contrast detection.”

The Johns Hopkins team along with other scientists conducted several experiments with mice and found that when melanopin was present in the retinal ganglion cells, the mice were better able to see contrast in a Y-shaped maze, known as the visual water task test. In the test, mice are trained to associate a pattern with a hidden platform that allows them to escape the water. Mice that had the melanopsin gene intact had higher contrast sensitivity than mice that lack the gene.

“Melanopsin signaling is essential for full contrast sensitivity in mouse visual functions,” said Hattar. “The ipRGCs and melanopsin determine the threshold for detecting edges in the visual scene, which means that visual functions that were thought to be solely mediated by rods and cones are now influenced by this system. The next step is to determine if melanopsin plays a similar role in the human retina for image-forming visual functions.”

A precise rhythm of electrical impulses transmitted from cells in the inner ear coaches the brain how to hear, according to a new study led by researchers at the University of Pittsburgh School of Medicine. They report the first evidence of this developmental process today in the online version of Neuron.

The ear generates spontaneous electrical activity to trigger a response in the brain before hearing actually begins, said senior investigator Karl Kandler, Ph.D., professor of otolaryngology and neurobiology, Pitt School of Medicine. These patterned bursts start at inner hair cells in the cochlea, which is part of the inner ear, and travel along the auditory nerve to the brain.

"It’s long been speculated that these impulses are intended to ‘wire’ the brain auditory centers," he said. "Until now, however, no one has been able to provide experimental evidence to support this concept."

To map neural connectivity, Dr. Kandler’s team prepared sections of a mouse brain containing the auditory pathways in a chemical that is inert until UV light hits it. Then, they pulsed laser light at a neuron, making the chemical active, which excites the nerve cells to generate an electrical impulse. They then tracked the spread of the impulse to adjacent cells, allowing them to map the network a neuron at a time.

All mice are born unable to hear, a sense that develops around two weeks after birth. But even before hearing starts, the ear produces rhythmic bursts of electrical activity which causes a broad reaction in the brain’s auditory processing centers. As the beat goes on, the brain organizes itself, pruning unneeded connections and strengthening others. To investigate whether the beat is indeed important for this reorganization, the team used genetically engineered mice that lack a key receptor on the inner hair cells which causes them to change their beat.

"In normal mice, the wiring diagram of the brain gets sharper and more efficient over time and they begin to hear," Dr. Kandler said. "But this doesn’t happen when the inner ear beats in a different rhythm, which means the brain isn’t getting the instructions it needs to wire itself correctly. We have evidence that these mice can detect sound, but they have problems perceiving the pitch of sounds."

In humans, such subtle hearing deficits are associated with Central Auditory-Processing Disorders (CAPD), difficulty processing the meaning of sound. About 2 to 3 percent of children are affected with CAPD and these children often have speech and language disorders or delays, and learning disabilities such as dyslexia. In contrast to causes of hearing impairments due to ear deficits, the causes underlying CAPD have remained obscure.

"Our findings suggest that an abnormal rhythm of electrical impulses early in life may be an important contributing factor in the development of CAPD. More research is needed to find out whether this also holds true for humans, but our results point to a new direction that is worth following up," Dr. Kandler said.

How does a DJ mix two songs to make the beat seem common to both tracks? A successful DJ makes the transition between tracks appear seamless while a bad mix is instantly noticeable and results in a ‘galloping horses’ effect that disrupts the dancing of the crowd. How accurate does beat mixing need to be to enhance, rather than disrupt perceived rhythm?

In a study published today (Wednesday 21 May 2014) in the journal Proceedings of the Royal Society B, scientists from the Universities of Birmingham and Cambridge present a new model that predicts whether or not two tracks will seem to share a common beat. This model also promises to help us understand how groups of people often start moving in synchrony, for example, football fans bouncing up and down at a stadium, or crowds falling into step when walking over a bridge.

‘We found that the time window in which two beat lines are heard as one isn’t fixed - it changes according to the statistical properties of each beat line, including how consistent or predictable they are,’ said Dr Mark Elliott, lead researcher on the study from the University of Birmingham’s School of Psychology. ‘For example, with two very consistent beat lines we only allow a very small time difference between them before we consider them to be separate. By analogy, given that DJs tend to play songs with a strong bass beat, they need to be very accurate in aligning the beats of the two songs if they are to be heard as one so as not to disrupt the flow of dancing. Our model and experiments reveal the timing properties of separate beat lines that determine whether they will be heard as one or two.’

Dr Elliott and his colleagues tested their model using a laboratory task that involved people tapping their fingers in time with two similar beat lines played simultaneously, one defined by high pitched tones, the other low pitched tones. The concurrency of the lines was varied such that the high and low pitched tones were played close together in time or far apart. Furthermore, the separation between the high-low tones was either consistent or randomly varied across the experiment. The researchers determined when people change from tapping along to a single beat formed from the two tones or targeted one of the tones while ignoring the other. They found that the time separation between tones that was required for people to judge them as distinct beats varied according to the consistency of the timings between the tones. Subsequently, these judgments influenced the timing of their movements.

Dr Elliott added, ‘People develop an expectation of when in time the next beat will occur. In defining the beat, they use the separation and consistency of the beat lines to determine whether the two tones should be combined together or whether just one tone should be attended to and the other ignored. Our model was able to predict the timing of participants’ movements based on the timing statistics of the tones we presented. Therefore, it not only allows us to calculate whether two beats will be heard as one, but also means we can predict the subtle effects the perception of an underlying rhythm can have on the movements people make to keep in synchrony with more complex beats.’

Dr Elliott is currently involved in a study, in collaboration with the University of Leeds, investigating the timing accuracy of movements in professional DJs compared to classical musicians and non-musicians. In addition, the findings of the current research are being applied to other areas: ‘We are currently investigating how spontaneous synchronisation of movements occurs within crowds. For example, in football stadiums the crowd sometimes starts to bounce up and down together. When the crowd moves together like this, it can create problems with structural vibration. Working with vibration engineers from the Universities of Sheffield and Exeter, we are applying our models to understand how such crowd dynamics might arise from the way each person adjusts their timing in relation to timing information from the people around them.’

In surprise findings, scientists at The Scripps Research Institute (TSRI) have discovered that a protein with a propensity to form harmful aggregates in the body when produced in the liver protects against Alzheimer’s disease aggregates when it is produced in the brain. The results suggest that drugs that can boost the protein’s production specifically in neurons could one day help ward off Alzheimer’s disease.

“This result was completely unexpected when we started this research,” said TSRI Professor Joel N. Buxbaum, MD. “But now we realize that it could indicate a new approach for Alzheimer’s prevention and therapy.”

Buxbaum and members of his laboratory report their latest finding in the May 21, 2014 issue of the Journal of Neuroscience.

First Hints

The study centers on transthyretin (TTR), a protein that is known to function as a transporter, carrying the thyroid hormone thyroxine and vitamin A through the bloodstream and cerebrospinal fluid. To do this job, it must come together in a four subunit structure called a tetramer. Certain factors such as old age and TTR gene mutations can make these tetramers prone to fall apart and misfold into tough aggregates called amyloids. TTR amyloids accumulate in the heart, kidneys, peripheral nerves and other tissues and cause life-shortening diseases including familial amyloid polyneuropathy and senile systemic (cardiac) amyloidosis.

Starting in the mid 1990s, however, reports from several laboratories hinted that TTR in the brain might protect against other amyloids—particularly the Alzheimer’s-associated protein amyloid beta. In test tube experiments, TTR seemed able to grab hold of amyloid beta and prevent it from aggregating. In transgenic “Alzheimer’s mice,” which overproduce amyloid beta, TTR expression was increased in affected brain tissue, compared to control mice, as one would expect from a protective response.

“I didn’t really believe those reports at the time,” Buxbaum said.

But he was working on TTR amyloidoses and had the tools needed to investigate the issue genetically. He and his colleagues at TSRI did those experiments, and found, to their surprise, that overproducing TTR in “Alzheimer’s mice” did indeed protect the animals: it reduced their memory deficits as well as the accumulations of amyloid beta aggregates in their brains. Since that 2008 study, Buxbaum and colleagues have gone on to publish additional experiments examining the mechanism of the protection including two last year, in collaboration with the Wright and Kelly laboratories at TSRI and Roberta Cascella in Florence, that showed how TTR tetramers can bind to amyloid beta and inhibit the latter from forming the more harmful types of aggregate.

Context Is Everything

In the latest study, Buxbaum and his team, including lead authors Xin Wang and Francesca Cattaneo, at the time both postdoctoral fellows in the Buxbaum laboratory, found another key piece of evidence for TTR’s protective role.

TTR is known to be produced principally in the liver and in the parts of the brain where cerebrospinal fluid is made. Prior studies in the Buxbaum group found evidence that TTR can also be produced in neurons, albeit at low levels. Still, it has remained unclear how TTR production, in neurons or in other cells, would be increased in response to amyloid beta accumulation.

To start, the team analyzed a segment of DNA near the TTR gene called the promoter region, where, in principle, special DNA-binding proteins called transcription factors could increase TTR gene activity. The analysis suggested that Heat Shock Factor 1 (HSF1), known as a master switch for a broad protective response against certain types of cellular stress, could bind to the TTR gene’s promoter.

Further experiments showed that HSF1 does indeed bind to this region and that two known stimulators of HSF1—heat and a compound called celastrol—also boost HSF1 binding to the TTR promoter, in addition to boosting TTR production. Remarkably, though, the researchers found that HSF1’s dialing-up of TTR production seemed to occur only in neuronal-type cells, not in liver cells where most TTR is produced.

In fact, the researchers found that in liver cells the HSF1 response somehow brought about a modest decrease in TTR production. That result may seem puzzling, but it is consistent with the idea that liver-cell TTR, which is produced at 15 to 20 times the levels of neuronal TTR, is more likely to be hazardous than protective.

Using genetic techniques to force cells to overproduce HSF1, the researchers again saw jumps in TTR gene activity and protein production, but only in neuronal cells. In liver cells TTR activity rose when HSF1 was blocked, suggesting that HSF1 normally helps keep a lid on liver TTR production.

“It’s becoming more and more evident in biology that the same molecule can do very different things in different contexts,” Buxbaum said.

To underscore the relevance to Alzheimer’s, his team examined neurons from the hippocampus brain region in ordinary lab mice and in amyloid-beta-overproducing Alzheimer’s mice. Again consistent with the concept of TTR as protective in neurons, they found that the frequency of HSF1 binding to the TTR gene promoter, and the numbers of resulting TTR gene transcripts, were both doubled in the Alzheimer’s mice compared to the ordinary lab mice.

Buxbaum and his colleagues plan to do further research on this apparent TTR-mediated stress response in neurons to determine, among other things, precisely how Alzheimer’s-associated amyloid beta switches it on. But they have already begun to think about developing a small molecule compound, suitable for delivery in a pill, that at least modestly boosts HSF1 activity and/or TTR production in neurons—and thus might prevent or delay Alzheimer’s dementia.

A molecular compound developed by Saint Louis University scientists restored learning, memory and appropriate behavior in a mouse model of Alzheimer’s disease, according to findings in the May issue of the Journal of Alzheimer’s Disease. The molecule also reduced inflammation in the part of the brain responsible for learning and memory.

The paper, authored by a team of scientists led by Susan Farr, Ph.D., research professor of geriatrics at Saint Louis University, is the second mouse study that supports the potential therapeutic value of an antisense compound in treating Alzheimer’s disease in humans.

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer’s disease," Farr said. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer’s disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the overexpression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in the brain of patients who have Alzheimer’s disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer’s disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus — the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1.

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object.

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

"Our findings reinforced the importance of amyloid beta protein in the Alzheimer’s disease process. They suggest that an antisense that targets the precursor to amyloid beta protein is a potential therapy to explore to reversing symptoms of Alzheimer’s disease," Farr said.

In his search to understand the role and function of brain waves, neuroscientist Ole Jensen (Radboud University) postulates a new theory on how the alpha wave controls attention to visual signals. His theory is published in Trends in Neurosciences on May 20. Alpha waves appear to be even more active and important than Jensen already thought.

Our brain cells ‘spark’ all the time. From this electronic activity brain waves emerge: oscillations at different band widths. And like a radio station uses different frequencies to carry specific information far away from the emitting source, so does the brain. And just like radio listeners with a certain musical preference tune in to the frequency that carries the music they prefer, brain area’s tune into the wave length relevant for their functioning.

Alpha waves aren’t boring
Ole Jensen, professor of Neuronal Oscillations at Radboud University’s Donders Institute for Brain, Cognition and Behaviour, tries to figure out how this network of sending and receiving information through oscillations works in detail. Earlier he discovered a novel role of the alpha wave that was long thought to be a boring wave, emerging when the brain runs idle and a person is dozing off. Jensen shifted this interpretation by showing the importance of the alpha frequency: it helps to shut down irrelevant brain area’s for a certain task. It helps us concentrate on what is really important at that moment.

To do list
In the Trends in Neurosciences paper that appeared today, Jensen postulates a new theory for how this actually works given a visual task. ‘We think that different phases of the alpha wave encode for different parts of a visual scene. It helps breaking down the visual information into small jobs and then perform those tasks in a specific order. A to do list for your visual attention system: focus on the face, focus on the hand, focus on the glass, look around. And then all over again.’

Jensen is now planning to test this new interpretation of the alpha wave in both animals and humans.

Scientists at the University of Pittsburgh School of Medicine have identified for the first time a key molecular mechanism by which the abnormal protein found in Huntington’s disease can cause brain cell death. The results of these studies, published today in Nature Neuroscience, could one day lead to ways to prevent the progressive neurological deterioration that characterizes the condition.

Huntington’s disease patients inherit from a parent a gene that contains too many repeats of a certain DNA sequence, which results in the production of an abnormal form of a protein called huntingtin (HTT), explained senior investigator Robert Friedlander, M.D., UPMC Professor of Neurosurgery and Neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But until now, studies have not suggested how HTT could cause disease.

“This study connects the dots for the first time and shows how huntingtin can cause problems for the mitochondria that lead to the death of neurons,” Dr. Friedlander said. “If we can disrupt the pathway, we may be able to identify new treatments for this devastating disease.”

Examination of brain tissue samples from both mice and human patients affected by Huntington’s disease showed that mutant HTT collects in the mitochondria, which are the energy suppliers of the cell. Using several biochemical approaches in follow-up mouse studies, the research team identified the mitochondrial proteins that bind to mutant HTT, noting its particular affinity for TIM23, a protein complex that transports other proteins from the rest of the cell into the mitochondria.

Further investigation revealed that mutant HTT inhibited TIM23’s ability to transport proteins across the mitochondrial membrane, slowing metabolic activity and ultimately triggering cell-suicide pathways. The team also found that mutant HTT-induced mitochondrial dysfunction occurred more often near the synapses, or junctions, of neurons, likely impairing the neuron’s ability to communicate or signal its neighbors.

To verify the findings, the researchers showed that producing more TIM23 could overcome the protein transport deficiency and prevent cell death.

“We learned also that these events occur very early in the disease process, not as the result of some other mutant HTT-induced changes,” Dr. Friedlander said. “This means that if we can find ways to intervene at this point, we may be able to prevent neurological damage.”

The team’s next steps include identifying exact binding sites and agents that can influence the interactions of HTT and TIM23.

Perhaps one of the keys to good health isn’t just what you eat but how you taste it.

Taste buds – yes, the same ones you may blame for that sweet tooth or French fry craving – may in fact have a powerful role in a long and healthy life – at least for fruit flies, say two new studies that appear in the Proceedings of the National Academy of Sciences of the United States of America.

Researchers from the University of Michigan, Wayne State University and Friedrich Miescher Institute for Biomedical Research in Switzerland found that suppressing the animal’s ability to taste its food –regardless of how much it actually eats – can significantly increase or decrease its length of life and potentially promote healthy aging.
 
Bitter tastes could have negative effects on lifespan, sweet tastes had positive effects, and the ability to taste water had the most significant impact – flies that could not taste water lived up to 43% longer than other flies. The findings suggest that in fruit flies, the loss of taste may cause physiological changes to help the body adapt to the perception that it’s not getting adequate nutrients.

In the case of flies whose loss of water taste led to a longer life, authors say the animals may attempt to compensate for a perceived water shortage by storing greater amounts of fat and subsequently using these fat stores to produce water internally. Further studies are planned to better explore how and why bitter and sweet tastes affect aging.

“This brings us further understanding about how sensory perception affects health. It turns out that taste buds are doing more than we think,” says senior author of the University of Michigan-led study Scott Pletcher, Ph.D., associate professor in the Department of Molecular and Integrative Physiology and research associate professor at the Institute of Gerontology.

“We know they’re able to help us avoid or be attracted to certain foods but in fruit flies, it appears that taste may also have a very profound effect on the physiological state and healthy aging.”
 
Pletcher conducted the study with lead author Michael Waterson, a Ph.D graduate student in U-M’s Cellular and Molecular Biology Program.  

“Our world is shaped by our sensory abilities that help us navigate our surroundings and by dissecting how this affects aging, we can lay the groundwork for new ideas to improve our health,” says senior author of the other study, Joy Alcedo, Ph.D, assistant professor in the Department of Biological Sciences at Wayne State University, formerly of the Friedrich Miescher Institute for Biomedical Research in Switzerland. Alcedo conducted the research with lead author Ivan Ostojic, Ph.D., of the Friedrich Miescher Institute for Biomedical Research in Switzerland.

Recent studies suggest that sensory perception may influence health-related characteristics such as athletic performance, type II diabetes, and aging. The two new studies, however, provide the first detailed look into the role of taste perception.

“These findings help us better understand the influence of sensory signals, which we now know not only tune an organism into its environment but also cause substantial changes in physiology that affect overall health and longevity,” Waterson says. “We need further studies to help us apply this knowledge to health in humans potentially through tailored diets favoring certain tastes or even pharmaceutical compounds that target taste inputs without diet alterations.”

In Parkinson’s disease (PD), dopamine-producing nerve cells that control our movements waste away. Current treatments for PD therefore aim at restoring dopamine contents in the brain. In a new study from Lund University, researchers are attacking the problem from a different angle, through early activation of a protein that improves the brain’s capacity to cope with a host of harmful processes. Stimulating the protein, called Sigma-1 receptor, sets off a battery of defence mechanisms and restores lost motor function. The results were obtained in mice, but clinical trials in patients may not be far away.

By activating the Sigma-1 receptor, a versatile protein involved in many cellular functions, levels of several molecules that help nerve cells build new connections increased, inflammation decreased, while dopamine levels also rose. The results, published in the journal Brain, show a marked improvement of motor symptoms in mice with a Parkinson-like condition that had been treated with a Sigma-1-stimulating drug for 5 weeks.

This treatment has never before been studied in connection with Parkinson’s disease. However, various publications linked to stroke and motor neurone disease have reported positive results with drugs that stimulate the Sigma-1 receptor, and a biotech company in the US will soon begin clinical trials on Alzheimer’s patients. The fact that substances stimulating this protein are already available for clinical use is a major advantage, according to Professor M. Angela Cenci Nilsson, head of the research team at Lund University.

“It is a huge advantage that these substances have already been tested in people and approved for clinical application. It means that we already know that the body tolerates this treatment. Clinical trials for Parkinson’s disease could theoretically start any time”.

Boosting the brain’s in-built defence mechanisms with approaches like this is a rather new idea in Parkinson’s research. Professor Cenci Nilsson, however, believes that the number of targets for future treatments is increasing as we learn more and more about the complex effects of PD on many different types of cells in the brain.

“The motor improvements we have seen in mice are disproportionately large compared to the recovery of dopamine levels. We believe this is because the treatment has protected the brain against a series of indirect consequences triggered by the Parkinson-like lesion. For example, we know today that a loss of dopamine causes the target neurons to lose synapses, and also alters both neural pathways and non-neuronal cells in the brain. Since the Sigma-1 receptor is widely expressed in many cell types, the treatment could intervene in many of these damaging processes “.

The treatment was shown to be significantly more effective when started at the beginning of the most aggressive phase of dopamine cell death. As a future potential therapy for Parkinson’s disease, this treatment would therefore need to be started as soon as possible after diagnosis in order to deliver maximum impact.

“In order to accelerate a possible clinical translation of our findings, we will now seek further evidence in support of this type of treatment. We are now discussing various opportunities with different collaborating partners, and we will try to procure funding for clinical studies in Parkinson´s disease as soon as possible”, concludes M. Angela Cenci Nilsson.

A biologist and a psychologist at the University of York have joined forces with a drug discovery group at Lundbeck in Denmark to develop a potential route to new therapies for the treatment of Parkinson’s Disease (PD).

Dr Chris Elliott, of the Department of Biology, and Dr Alex Wade, of the Department of Psychology, have devised a technique that could both provide an early warning of the disease and result in therapies to mitigate its symptoms.

In research reported in Human Molecular Genetics, they created a more sensitive test which detected neurological changes before degeneration of the nervous system became apparent.

In laboratory tests using fruit flies, the researchers discovered that a human genetic mutation that causes Parkinson’s amplified visual signals in young flies dramatically. This resulted in loss of vision in later life.

Working with researchers from the Danish pharmaceutical company, H.Lundbeck A/S, they tested a new drug that targets the Parkinson’s mutation in flies. This drug prevented the abnormal changes in the flies’ visual function.

It is the first time that the compound has been used in vivo and its effectiveness was analysed using the new, sensitive technique devised by Dr Wade. This was originally used for measuring vision in people with eye disease and epilepsy.

Dr Elliott, who is part-funded by Parkinson’s UK, said: “If this kind of drug proves to be successful in clinical trials, it would have the potential to bring long-lasting relief from PD symptoms and fewer side effects than existing levadopa therapy.”

Dr Wade added: “This technique forms a remarkable bridge between human clinical science and animal research. If it proves successful in the future, it could open the door to a new way of studying a whole range of neurological diseases.”

Senior Vice President, Research at Lundbeck, Kim Andersen, said:  “This new research may prove to be groundbreaking in the understanding and treatment of Parkinson’s disease. Science does not currently have answers for what happens in the brain before and during the disease, but these discoveries may bring us closer to this understanding. This may also give us the opportunity to revolutionize the diagnosis and treatment of Parkinson’s disease, for the benefit of patients and their families.”

Mice crippled by an autoimmune disease similar to multiple sclerosis (MS) regained the ability to walk and run after a team of researchers led by scientists at The Scripps Research Institute (TSRI), University of Utah and University of California (UC), Irvine implanted human stem cells into their injured spinal cords.

Remarkably, the mice recovered even after their bodies rejected the human stem cells. “When we implanted the human cells into mice that were paralyzed, they got up and started walking a couple of weeks later, and they completely recovered over the next several months,” said study co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.

Thomas Lane, an immunologist at the University of Utah who co-led the study with Loring, said he had never seen anything like it. “We’ve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring’s lab provided,” said Lane, who began the study at UC Irvine.

The mice’s dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans.

"This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients,” said co-author Craig Walsh, a UC Irvine immunologist.

Stem Cell Therapy for MS

MS is an autoimmune disease of the brain and spinal cord that affects more than a half-million people in North America and Europe, and more than two million worldwide. In MS, immune cells known as T cells invade the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating on nerve fibers called myelin. Affected nerve fibers lose their ability to transmit electrical signals efficiently, and this can eventually lead to symptoms such as limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression.

Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers. But they are only partially effective and often have significant adverse side effects. Loring’s group at TSRI has been searching for another way to treat MS using human pluripotent stem cells, which are cells that have the potential to transform into any of the cell types in the body.

Loring’s group has been focused on turning human stem cells into neural precursor cells, which are an intermediate cell type that can eventually develop into neurons and other kinds of cells in the nervous system. In collaboration with Lane’s group, Loring’s team has been testing the effects of implanting human neural precursor cells into the spinal cords of mice that have been infected with a virus that induces symptoms of MS.

A Domino Effect

The transformation that took place in the largely immobilized mice after the human neural precursor cells were injected into the animals’ damaged spinal cords was dramatic. “Tom called me up and said, ‘You’re not going to believe this,’” Loring said. “He sent me a video, and it showed the mice running around the cages. I said, ‘Are you sure these are the same mice?’”

Even more remarkable, the animals continued walking even after the human cells were rejected, which occurred about a week after implantation. This suggests that the human stem cells were secreting a protein or proteins that had a long-lasting effect on preventing or impeding the progression of MS in the mice, said Ron Coleman, a TSRI graduate student in Loring’s lab who was first author of the paper with Lu Chen of UC Irvine. “Once the human stem cells kick that first domino, the cells can be removed and the process will go on because they’ve initiated a cascade of events,” said Coleman.

The scientists showed in the new study that the implanted human stem cells triggered the creation of white blood cells known as regulatory T cells, which are responsible for shutting down the autoimmune response at the end of an inflammation. In addition, the implanted cells released proteins that signaled cells to re-myelinate the nerve cells that had been stripped of their protective sheaths.

A Happy Accident

The particular line of human neural precursor cells used to heal the mice was the result of a lucky break. Coleman was using a common technique for coaxing human stem cells into neural precursor cells, but decided partway through the process to deviate from the standard protocol. In particular, he transferred the developing cells to another Petri dish.

“I wanted the cells to all have similar properties, and they looked really different when I didn’t transfer them,” said Coleman, who was motivated to study MS after his mother died from the disease. This step, called “passaging,” proved key. “It turns out that passaging alters the types of proteins that the cells express,” he said.

Loring called the creation of the successful neural precursor cell line a “happy accident.” “If we had used common techniques to create the cells, they wouldn’t have worked,” she said. “We’ve shown that now. There are a dozen different ways to make neural precursor cells, and only this one has worked so far. We now know that it is incredibly important to make the cells the same way every time.”

Hot On the Trail

The team is now working to discover the particular proteins that its unique line of human precursor cells release. One promising candidate is a class of proteins known as transforming growth factor beta, or TGF-B, which other studies have shown is involved the creation of regulatory T cells. Experiments by the scientists showed that the human neural precursor cells released TGF-B proteins while they were inside the spinal cords of the impaired mice. However, it’s also likely that other, as yet unidentified, protein factors may also be involved in the mice’s healing.

If the team can pinpoint which proteins released by the neural precursor cells are responsible for the animals’ recovery, it may be possible to devise MS treatments that don’t involve the use of human stem cells. “Once we identify the factors that are responsible for healing, we could make a drug out of them,” said Lane. Another possibility, Loring said, might be to infuse the spinal cords of humans affected by MS with the protein factors that promote healing.

A better understanding of what makes these human neural precursor cells effective in mice will be key to developing either of these therapies for humans. “We’re on the trail now of what these cells do and how they work,” Loring said.