Neuroscience

Scientists from the Montreal Neurological Institute and Hospital in Canada have discovered that two genes linked to hereditary Parkinson’s disease are involved in the early-stage quality control of mitochondria. The protective mechanism, which is reported in The EMBO Journal, removes damaged proteins that arise from oxidative stress from mitochondria.

“PINK1 and parkin, are implicated in selectively targeting dysfunctional components of mitochondria to the lysosome under conditions of excessive oxidative damage within the organelle,” said Edward Fon, Professor at the McGill Parkinson Program at the Montreal Neurological Institute and Hospital.  “Our study reveals a quality control mechanism where vesicles bud off from mitochondria and proceed to the lysosome for degradation. This method is distinct from the degradation pathway for damaged whole mitochondria which has been known for some time. It is also an early response, proceeding on a timescale of hours instead of days.”

The deterioration of mechanisms designed to maintain the integrity and function of mitochondria throughout the lifetime of a cell has been suggested to underlie the progression of several neurodegenerative diseases, including Parkinson’s disease. When mitochondria, the “power plants” of the cell that provide energy, malfunction they can contribute to Parkinson’s disease. If they are to survive and function mitochondria need to degrade oxidized and damaged proteins.

In the study, immunofluorescence and confocal microscopy were used to observe how the vesicles “pinch off” from mitochondria with their damaged cargo. “Our conclusion is that the loss of this PINK1 and parkin-dependent trafficking system impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins and leads, over time, to the mitochondrial dysfunction noted in hereditary Parkinson’s disease,” said Heidi McBride, Professor in the Neuromuscular Group in the Department of Neurology and Neurosurgery at the Montreal Neurological Institute and Hospital.

Both salvage pathways are operational in the cell. If the vesicular pathway, the first line of defense, is overwhelmed and the damage is irreversible then the entire organelle is targeted for degradation.

Cleveland Clinic researchers have identified a protein in the brain that plays a critical role in the memory loss seen in Alzheimer’s patients, according to a study to be published in the journal Nature Neuroscience and posted online today.

The protein – Neuroligin-1 (NLGN1) – is known to be involved in memory formation; this is the first time it’s been linked to amyloid-associated memory loss.

In Alzheimer’s disease, amyloid beta proteins accumulate in the brains of Alzheimer’s patients and induce inflammation. This inflammation leads to certain gene modifications that interrupt the functioning of synapses in the brain, leading to memory loss.

Using animal models, Cleveland Clinic researchers have discovered that during this neuroinflammatory process, the epigenetic modification of NLGN1 disrupts the synaptic network in the brain, which is responsible for developing and maintaining memories. Destroying this network can lead to the type of memory loss seen in Alzheimer’s patients.

"Alzheimer’s is a challenging disease that researchers have been approaching from all angles," said Mohamed Naguib, M.D., the Cleveland Clinic physician who lead the study. "This discovery could provide us with a new approach for preventing and treating Alzheimer’s disease."

Previous studies from this group of researchers have also identified a novel compound called MDA7, which can potentially stop the neuroinflammatory process that leads to the modification of NLGN1. Treatment with the compound restored cognition, memory and synaptic plasticity – a key neurological foundation of learning and memory – in an animal model. Significant preliminary work for the first-in-man study has been completed for MDA7 including in-vitro studies and preliminary clinical toxicology and pharmacokinetic work. The Cleveland Clinic plans to initiate Phase I human studies on the safety of this class of compounds in the near future.

Alzheimer’s disease is an irreversible, fatal brain disease that slowly destroys memory and thinking skills. About 5 million people in the United States have Alzheimer’s disease. With the aging of the population, and without successful treatment, there will be 16 million Americans and 106 million people worldwide with Alzheimer’s by 2050, according to the 2011 Alzheimer’s Disease Facts and Figures report from the Alzheimer’s Association.

Memories of traumatic events often last a lifetime because they are so difficult to treat through behavioral approaches. A preclinical study in mice published by Cell Press January 16th in the journal Cell reveals that drugs known as histone deacetylase inhibitors (HDACis) can enhance the brain’s ability to permanently replace old traumatic memories with new memories, opening promising avenues for the treatment of posttraumatic stress disorder (PTSD) and other anxiety disorders.

Caption: Metabolic activity (green and red colors) in the hippocampus (white dotted line) of animals that underwent extinction training in combination with HDACis (right) is significantly higher than in animals that underwent extinction training alone (left). Metabolic activity serves to estimate the learning capacity of an animal. Credit: Cell, Gräff et al.

"Psychotherapy is often used for treating PTSD, but it doesn’t always work, especially when the traumatic events occurred many years earlier," says senior study author Li-Huei Tsai of the Massachusetts Institute of Technology. "This study provides a mechanism explaining why old memories are difficult to extinguish and shows that HDACis can facilitate psychotherapy to treat anxiety disorders such as PTSD."

One common treatment for anxiety disorders is exposure-based therapy, which involves exposing patients to fear-evoking thoughts or events in a safe environment. This process reactivates the traumatic memory, opening a short time window during which the original memory can be disrupted and replaced with new memories. Exposure-based therapy is effective when the traumatic events occurred recently, but until now, it was not clear whether it would also be effective for older traumatic memories.

To address this question, Tsai and her team used a protocol for studying fear responses associated with traumatic memories. In the first phase, the researchers exposed mice to a tone followed by an electrical footshock. Once the mice learned to associate these two events, they began to freeze in fear upon hearing the tone by itself, even when they did not receive a shock. Using an extinction protocol, which is similar to exposure-based therapy, the researchers repeatedly presented the tone without the shock to test whether the mice could unlearn the association between these two events and would stop freezing in response to the tone. The extinction protocol was successful for mice that were exposed to the tone-shock pairing just one day earlier, but it was not effective for mice that originally formed the traumatic memory one month earlier. The researchers hypothesized that epigenetic modification of genes involved in learning and memory might be responsible for the diminished response of treatment for older memories.

The researchers tested whether HDACis, which promote long-lasting activation of genes involved in learning and memory, could help replace old traumatic memories with new memories. Mice previously exposed to the tone-shock pairing received HDACis and then underwent the extinction protocol. These mice learned to stop freezing in response to the tone, even when they originally formed the traumatic memory one month earlier. “Collectively, our findings suggest that exposure-based therapy alone does not effectively weaken traumatic memories that were formed a long time ago, but that HDACis can be combined with exposure-based therapy to substantially improve treatment for the most enduring traumatic memories,” Tsai says.

An Auburn University researcher teamed up with the National Institutes of Health to study how brain networks shape an individual’s religious belief, finding that brain interactions were different between religious and non-religious subjects.

Gopikrishna Deshpande, an assistant professor in the Department of Electrical and Computer Engineering in Auburn’s Samuel Ginn College of Engineering, and the NIH researchers recently published their results in the journal, “Brain Connectivity.”

The group found differences in brain interactions that involved the theory of mind, or ToM, brain network, which underlies the ability to relate between one’s personal beliefs, intents and desires with those of others. Individuals with stronger ToM activity were found to be more religious. Deshpande says this supports the hypothesis that development of ToM abilities in humans during evolution may have given rise to religion in human societies.

“Religious belief is a unique human attribute observed across different cultures in the world, even in those cultures which evolved independently, such as Mayans in Central America and aboriginals in Australia,” said Deshpande, who is also a researcher at Auburn’s Magnetic Resonance Imaging Research Center. “This has led scientists to speculate that there must be a biological basis for the evolution of religion in human societies.”

Deshpande and the NIH scientists were following up a study reported in the Proceedings of the National Academy of Sciences, which used functional magnetic resonance imaging, or fMRI, to scan the brains of both self-declared religious and non-religious individuals as they contemplated three psychological dimensions of religious beliefs.

The fMRI – which allows researchers to infer specific brain regions and networks that become active when a person performs a certain mental or physical task – showed that different brain networks were activated by the three psychological dimensions; however, the amount of activation was not different in religious as compared to non-religious subjects.

A world-first study led by the National Cannabis Prevention and Information Centre (NCPIC) at UNSW has revealed a breakthrough for dependent cannabis users, employing a cannabis-based medication, Sativex (nabiximols), that has been shown to provide significant relief from withdrawal symptoms.

“One in ten people who try cannabis go on to become dependent. As cannabis use increases around the world and more people seek treatment to help them quit, it is surprising there is no approved medication to alleviate symptoms of withdrawal. The success of this study offers considerable hope for those struggling to get through a cannabis withdrawal and remain abstinent into the future,” said Professor Jan Copeland, Director of NCPIC and Chief Investigator of the study.

“One of the greatest barriers to quitting cannabis is withdrawal and while symptoms aren’t life-threatening, they are of a severity level that causes marked distress. For many people, symptoms including irritability, depression, cannabis cravings and sleep problems, can overcome their strong desire to quit and they find themselves using again.”

The study was conducted at inpatient services of South Eastern Sydney and Hunter New England Local Health Districts.

Associate Professor Nicolas Lintzeris, Director of Drug and Alcohol Services at South Eastern Sydney Local Health District and a trial investigator said: “The study found patients treated with Sativex stayed in treatment longer, and experienced a shorter and milder withdrawal than patients receiving placebo.”

Administered as an oral spray, Sativex is only licensed in Australia for the treatment of spasticity and pain in Multiple Sclerosis (MS) patients when other medications have failed. The spray contains the cannabis extracts, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), which is the substance primarily responsible for the psychoactive effects of cannabis.

The lead author of the paper and study investigator Dr David Allsop noted, “While most people who use cannabis do not become dependent, those who use regularly or for an extended period run that risk. Sativex is not licensed or available for treating cannabis users at this time. Our hope is that this study will lead to further research, and possibly approval of the drug for use as a treatment for people experiencing problematic cannabis use.”

The full findings of this study have been published in international psychiatry journal, JAMA Psychiatry.

A new study by scientists at McGill University and the University of Zurich shows a direct link between metabolism in brain cells and their ability to signal information. The research may explain why the seizures of many epilepsy patients can be controlled by a specially formulated diet. 

(Image caption: Neurons in the cerebellum. Credit: Bowie Lab/McGill University)

The findings, published Jan. 16 in Nature Communications, reveal that metabolism controls the processes that inhibit brain activity, such as that involved in convulsions. The study uncovers a link between how brain cells make energy and how the same cells signal information – processes that neuroscientists have often assumed to be distinct and separate. 

“Inhibition in the brain is commonly targeted in clinical practice,” notes Derek Bowie, Canada Research Chair in Receptor Pharmacology at McGill and corresponding author of the study. “For example, drugs that alleviate anxiety, induce anesthesia, or even control epilepsy work by strengthening brain inhibition. These pharmacological approaches can have their drawbacks, since patients often complain of unpleasant side effects.” 

The experiments showed an unexpected link between how the mitochondria of brain cells make energy and how the same cells signal information. Brain cells couple these two independent functions by using small chemical messengers, called reactive oxygen species (or ROS), that are normally associated with signaling cell death. While ROS are known to have roles in diseases of aging, such as Alzheimer’s and Parkinson’s, the new study shows they also play important roles in the healthy brain.  

The findings emerged from an ongoing collaboration between Prof. Bowie’s laboratory in McGill’s Department of Pharmacology and Therapeutics and a research team headed by Dr. Jean-Marc Fritschy, Professor of Pharmacology at the University of Zurich and current director of the Neuroscience Center Zurich (ZNZ). The researchers have the longer term aim of trying to understand why the seizures of many epilepsy patients — especially young children – can be treated with a high-fat, low-carbohydrate diet known as the ketogenic diet. 

The idea that diet can control seizures was noticed as far back as ancient Greece, during periods of fasting. From the 1920s until the 1950s, the ketogenic diet was widely used to treat epilepsy patients. With the introduction of anticonvulsant drugs in the 1950s, the dietary approach fell out of favour with doctors. But because anticonvulsant drugs don’t work for 20% to 30% of patients, there has been a resurgence in use of the ketogenic diet. 

“Since our study shows that brain cells have their own means to strengthen inhibition,” explains Prof Bowie, “our work points to potentially new ways in which to control a number of important neurological conditions including epilepsy.”

Middle-aged men who drink more than 36 grams of alcohol, or two and a half US drinks per day, may speed their memory loss by up to six years later on, according to a study published in the January 15, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology. On the other hand, the study found no differences in memory and executive function in men who do not drink, former drinkers and light or moderate drinkers. Executive function deals with attention and reasoning skills in achieving a goal.

“Much of the research evidence about drinking and a relationship to memory and executive function is based on older populations,” said study author Séverine Sabia, PhD, of the University College London in the United Kingdom. “Our study focused on middle-aged participants and suggests that heavy drinking is associated with faster decline in all areas of cognitive function in men.”

The study involved 5,054 men and 2,099 women whose drinking habits were assessed three times over 10 years. A drink was considered wine, beer or liquor. Then, when the participants were an average age of 56, they took their first memory and executive function test. The tests were repeated twice over the next 10 years.

The study found that there were no differences in memory and executive function decline between men who did not drink and those who were light or moderate drinkers—those who drank less than 20 grams, or less than two US drinks per day. Heavy drinkers showed memory and executive function declines between one-and-a-half to six years faster than those who had fewer drinks per day.

Survivors of traumatic brain injuries (TBI) are three times more likely to die prematurely than the general population, often from suicide or fatal injuries, finds an Oxford University-led study.

A TBI is a blow to the head that leads to a skull fracture, internal bleeding, loss of consciousness for longer than an hour or a combination of these symptoms. Michael Schumacher’s recent skiing injury is an example of a TBI. Concussions, sometimes called mild TBIs, do not present with these symptoms and were analysed separately in this study.

Researchers examined Swedish medical records going back 41 years covering 218,300 TBI survivors, 150,513 siblings of TBI survivors and over two million control cases matched by sex and age from the general population. The work was carried out by researchers at Oxford University and the Karolinska Institute in Stockholm.

'We found that people who survive six months after TBI remain three times more likely to die prematurely than the control population and 2.6 times more likely to die than unaffected siblings,' said study leader Dr Seena Fazel, a Wellcome Trust Senior Research Fellow in Oxford University's Department of Psychiatry. 'Looking at siblings who did not suffer TBIs allows us to control for genetic factors and early upbringing, so it is striking to see that the effect remains strong even after controlling for these.'

The results, published in the journal JAMA Psychiatry, show that TBI survivors who also have a history of substance abuse or psychiatric disorders are at highest risk of premature death. Premature deaths were defined as before age 56. The main causes of premature death in TBI survivors are suicide and fatal injuries such as car accidents and falls.

'TBI survivors are more than twice as likely to kill themselves as unaffected siblings, many of whom were diagnosed with psychiatric disorders after their TBI,' said Dr Fazel. 'Current guidelines do not recommend assessments of mental health or suicide risk in TBI patients, instead focusing on short-term survival. Looking at these findings, it may make more sense to treat some TBI patients as suffering from a chronic problem requiring longer term management just like epilepsy or diabetes. TBI survivors should be monitored carefully for signs of depression, substance abuse and other psychiatric disorders, which are all treatable conditions.'

The exact reasons for the increased risk of premature death are unknown but may involve damage to the parts of the brain responsible for judgement, decision making and risk taking. TBI survivors are three times more likely to die from fatal injuries which may be a result of impaired judgement or reactions.

'This study highlights the important and as yet unanswered question of why TBI survivors are more likely to die young, but it may be that serious brain trauma has lasting effects on people's judgement,' suggests Dr Fazel. 'People who have survived the acute effects of TBI should be more informed about these risks and how to reduce their impact.'

'When treating traumatic brain injuries focus is placed on immediate treatment and recovery of patients,' says Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust. 'This new finding offers important insight into the longer-term impact of TBIs on the brain and their effect on survival later in life. We hope that further research into understanding which parts of the brain are responsible will help improve future management programmes and reduce the potential for premature death.'

Even relatively minor brain injuries, concussions, had a significant impact on early mortality. People with concussion were found to be twice as likely to die prematurely as the control population, with suicide and fatal injuries as the main causes of death. This raises issues surrounding concussions in a wide range of sports, from American football, rugby and soccer to baseball and cricket.

We use both sides of our brain for speech, a finding by researchers at New York University and NYU Langone Medical Center that alters previous conceptions about neurological activity. The results, which appear in the journal Nature, also offer insights into addressing speech-related inhibitions caused by stroke or injury and lay the groundwork for better rehabilitation methods.

“Our findings upend what has been universally accepted in the scientific community—that we use only one side of our brains for speech,” says Bijan Pesaran, an associate professor in NYU’s Center for Neural Science and the study’s senior author. “In addition, now that we have a firmer understanding of how speech is generated, our work toward finding remedies for speech afflictions is much better informed.”

Many in the scientific community have posited that both speech and language are lateralized—that is, we use only one side of our brains for speech, which involves listening and speaking, and language, which involves constructing and understanding sentences. However, the conclusions pertaining to speech generally stem from studies that rely on indirect measurements of brain activity, raising questions about characterizing speech as lateralized.

To address this matter, the researchers directly examined the connection between speech and the neurological process.

Specifically, the study relied on data collected at NYU ECoG, a center where brain activity is recorded directly from patients implanted with specialized electrodes placed directly inside and on the surface of the brain while the patients are performing sensory and cognitive tasks. Here, the researchers examined brain functions of patients suffering from epilepsy by using methods that coincided with their medical treatment.

“Recordings directly from the human brain are a rare opportunity,” says Thomas Thesen, director of the NYU ECoG Center and co-author of the study.

“As such, they offer unparalleled spatial and temporal resolution over other imaging technologies to help us achieve a better understanding of complex and uniquely human brain functions, such as language,” adds Thesen, an assistant professor at NYU Langone.

In their examination, the researchers tested the parts of the brain that were used during speech. Here, the study’s subjects were asked to repeat two “non-words”—“kig” and “pob.” Using non-words as a prompt to gauge neurological activity, the researchers were able to isolate speech from language.

An analysis of brain activity as patients engaged in speech tasks showed that both sides of the brain were used—that is, speech is, in fact, bi-lateral.

“Now that we have greater insights into the connection between the brain and speech, we can begin to develop new ways to aid those trying to regain the ability to speak after a stroke or injuries resulting in brain damage,” observes Pesaran. “With this greater understanding of the speech process, we can retool rehabilitation methods in ways that isolate speech recovery and that don’t involve language.”

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have described a pair of drug candidates that advance the search for new treatments for pain, addiction and other disorders.

The two new drug scaffolds, described in a recent edition of The Journal of Biological Chemistry, offer researchers novel tools that act on a demonstrated therapeutic target, the kappa opioid receptor (KOR), which is located on nerve cells and plays a role in the release of the neurotransmitter dopamine. While compounds that activate KOR are associated with positive therapeutic effects, they often also recruit a molecule known as βarrestin2 (beta arrestin), which is associated with depressed mood and severely limits any therapeutic potential.

“Compounds that act at kappa receptors may provide a means for treating addiction and for treating pain; however, there is the potential for the development of depression or dysphoria associated with this receptor target,” said Laura Bohn, a TSRI associate professor who led the study. “There is evidence that the negative feelings caused by kappa receptor drugs may be, in part, due to receptor actions through proteins called beta arrestins. Developing compounds that activate the receptors without recruiting beta arrestin function may serve as a means to improve the therapeutic potential and limit side effects.”

The new compounds are called “biased agonists,” activating the receptor without engaging the beta arrestins.

Research Associate Lei Zhou, first author of the study with Research Associate Kimberly M. Lovell, added, “The importance of these biased agonists is that we can manipulate the activation of one particular signaling cascade that produces analgesia, but not the other one that could lead to dysphoria or depression.”

The researchers note that the avoidance of depression is particularly important in addiction treatment, where depressed mood can play a role in relapse. 

The two drug candidates also have a high affinity and selectivity for KOR over other opioid receptors and are able to pass through the blood-brain barrier. Given these promising attributes, the scientists plan to continue developing the compounds.

When an MRI scan uncovers an unusual architecture or shape in a child’s brain, it’s cause for concern: The malformation may be a sign of disease. But deciding whether that odd-looking anatomy is worrisome or harmless can be difficult. To help doctors reach the right decision, Johns Hopkins researchers are building a detailed digital library of MRI scans collected from children with normal and abnormal brains. The goal, the researchers say, is to give physicians a Google-like search system that will enhance the way they diagnose and treat young patients with brain disorders.

This cloud-computing project, being developed by a team of engineers and radiologists, should allow physicians to access thousands of pediatric scans to look for some that resemble their own patient’s image. The project is supported by a three-year $600,000 grant from the National Institutes of Health.

"We’re creating a pediatric brain data bank that will let doctors look at MRI brain scans of children who have already been diagnosed with illnesses like epilepsy or psychiatric disorders," said Michael I. Miller, a lead investigator on the project. "It will provide a way to share important new discoveries about how changes in brain structures are linked to brain disorders. For the medical imaging world, this system will do what a search engine like Google does when you ask it to look for specific information on the Web."

Miller, a pioneer in the field of computational anatomy, the technology used for “brain parsing,” is the Herschel and Ruth Seder Professor of Biomedical Engineering at Johns Hopkins and director of the university’s Center for Imaging Science. He also is a core faculty member in the university’s Institute for Computational Medicine.

The new pediatric brain imaging data bank, Miller said, will be useful in at least two ways.

"If doctors aren’t sure which disease is causing a child’s condition, they could search the data bank for images that closely match their patient’s most recent scan," he said. "If a diagnosis is already attached to an image from the data bank that could steer the physician in the right direction. Also, the scans in our library may help a physician identify a change in the shape of a brain structure that occurs very early in the course of a disease, even before clinical symptoms appear. That could allow the physician get an early start on the treatment."

Miller’s co-lead investigator on the project is Susumu Mori, a professor of radiology in the Johns Hopkins School of Medicine. One of Mori’s primary research interests is studying the anatomy of brain structures captured in MRI scans. 

Mori points out that such a “biobank” has the potential to impact doctors’ workflow dramatically.

"We empirically know that a certain type of anatomical abnormality is related to specific brain diseases," he said. "This relationship, however, is not always clear and often is compounded by anatomical changes during the normal course of brain development. Therefore, neuro-radiologists need extensive training to accumulate the knowledge. We hope our brain imaging data bank will not only assist such a learning process but also enhance the physician’s ability to understand the pathology and reach the best medical decision."

Mori and his collaborator, Thierry Huisman, a professor of radiology and pediatrics and the director of pediatric radiology at the Johns Hopkins Children’s Center, have been working for more than four years to establish a clinical database of more than 5,000 whole-brain MRI scans of children treated at Johns Hopkins. The patients’ names and other identifying information were withheld, but details related to their medical conditions were included. The computer software indexed anatomical information involving up to 1,000 structural measurements in 250 regions of the brain. These images were also sorted into 22 brain disease categories, including chromosomal abnormalities, congenital malformations, vascular diseases, infections, epilepsy and psychiatric disorders.

According to Huisman, the new data bank now under development not only facilitates recognition and correct classification of pediatric brain disorders, but the more objective image analysis also allows identification of injury and disease that may go undetected by the classical, more subjective radiological “eyeballing” of MR images. Furthermore, he said, recognition of distinct patterns of injury and the subsequent grouping of these children based upon their characteristic patterns of MRI findings allow recognition and identification of new diseases as well as reclassification of previously unclassified diseases. Finally, he added, the data acquisition is free of ionizing radiation, allowing doctors to study the most vulnerable, youngest patients and perhaps to help initiate disease-specific treatment before irreversible injury to the developing brain occurs.

Beyond the brain imaging data bank for children, the researchers have begun building a similar MRI brain image library with Marilyn Albert, a Johns Hopkins neurology professor. This library focuses on brain disorders commonly found in elderly patients. That project is associated with the National Institute of Aging’ Alzheimer’s Disease Research Center.

With all of this data in place, physicians will be able to conduct a Google-like search for images associated with normal and abnormal pediatric and aging brain conditions. For example, a physician who is uncertain about a child’s diagnosis could submit that patient’s latest brain scan and request the medical records of children with similar images. Alternatively, for studying neurodegenerative diseases such as Alzheimer’s in aging patients, a physician might ask to see the medical records associated with all images that display neurofibrillary tangles in the temporal lobe, a condition seen in his or her patient’s scan.

Jonathan Lewin, the chairman and radiologist-in-chief of the Johns Hopkins Department of Radiology and Radiological Science, noted that this approach could help patients with both common and uncommon diseases. “This research is one of the first real applications of ‘Big Data’ analytics, taking medical information from large numbers of patients, removing anything that would identify specific individuals, and then bringing the data into the ‘cloud’ to allow very high-powered analysis,” Lewin said. “This has been a goal of the medical community for almost a decade, and professors Miller and Mori have found a way to implement this technology in a manner that can bring its benefit to our patients, and can assist in the classification and identification of rare and subtle brain disorders as well as uncommon manifestations of more common diseases of the brain.”

Currently, the pilot pediatric brain imaging data bank is limited to physicians and patients within the Johns Hopkins medical system, but the researchers say the data bank could be expanded or replicated elsewhere in coming years.

A new form of cell sub-division that is key to the development of the nervous system has been identified by researchers at the University of Dundee.

Image caption: Image shows two newborn neurons shedding their tip ends, or abscising

Neurons are vital to the development of the nervous system and in some regions of our brains they are continually produced throughout our lives. They are ‘born’ in a particular place in the early nervous system and then have to migrate to the correct place to make functional neural structures.

A team led by Professor Kate Storey and Dr Raman Das in the College of Life Sciences at Dundee have now identified a new process, apical abscission, which mediates the detachment of new-born neurons from the neural tube ventricle - freeing these cells to migrate.

'Neuron production is an important process within our bodies. As an example, our memory centre, the hippocampus, continues to produce neurons throughout our lives,' said Professor Storey.

'What we have identified are the molecular events, the 'letting-go' process, which allow newborn neurons to move to their correct place in the nervous system.

'This is a new form of cell sub-division so it is of significant interest as it tells us about mechanisms that control how we develop that we didn't know before. We were very surprised when we first saw cells shedding their tip-ends as they began to differentiate into neurons, it is not what we had expected at all.

'Our discovery comes with the development of novel live-tissue imaging approaches in my lab, which allows us to monitor cell behaviour over long periods. We have also been to make use of state of the art super-resolution microscopy in the Light Microscopy Facility based here within the College of Life Sciences.'

The research has been funded by the Wellcome Trust and the results are published this week in the journal Science.

The work identifies molecular events that control the shedding of the cell’s tip. It takes place as cells lose a key adhesion molecule and involves increased activity of a cell constriction mechanism.

Surprisingly, this event, also involves dismantling of an important structure in the cell, the primary cilium, known to convey signals that promote cell proliferation. Das and Storey propose that Apical Abscission mediates a pivotal cell state transition in the neuronal differentiation process, rapidly altering the polarity and signalling activity of the new-born neuron.

The researchers plan to extend the work to determine if this new mechanism also operates in other contexts including different regions of the brain, but will also address if this takes place in some cancers, where cells are known to lose polarity, shed primary cilia and detach from their neighbours as a prelude to tissue invasion.

'We need to look more widely now to establish whether this regulated mechanism allows other cells to make rapid cell state transitions and to move in other tissues of the body,' said Professor Storey.

Producing brightly speckled red and green snapshots of many different tissues, Johns Hopkins researchers have color-coded cells in female mice to display which of their two X chromosomes has been made inactive, or “silenced.”

(Image caption: Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice (clockwise). Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. Hao Wu, courtesy of Neuron)

Scientists have long known that the silencing of one X chromosome in females — who have two X chromosomes in every cell — is a normal occurrence whose consequences can be significant, especially if one X chromosome carries a normal copy of a gene and the other X chromosome carries a mutated copy.

By genetically tagging different X chromosomes with genes that code for red or green fluorescent proteins, scientists say they can now peer into different tissue types to analyze genetic diversity within and between individual females at a new level of detail.

Published on Jan. 8 in the journal Neuron, a summary of the research shows wide-ranging variation in patterns of so-called X chromosome inactivation at every level: within tissues, on the left or right sides of a centrally located tissue (like the brain), among different tissue types, between paired organs (like the eyes) and among individuals.

"Calico cats, which are only ever female, have mottled coat colors. They have two different versions of a gene for coat color, which is located on the X chromosome: one version from their mother and the other from their father," explains Jeremy Nathans, M.D., Ph.D., professor of molecular biology and genetics at the Johns Hopkins University and a Howard Hughes Medical Institute investigator. "Their fur is orange or black depending on which X chromosome is silenced in a particular patch of skin cells. X chromosome inactivation actually occurs in all cells in female mammals, including humans, and it affects most of the genes on the X chromosome. Although this phenomenon has been known for over 50 years, it couldn’t be clearly visualized in internal organs and tissues until now."

Nathans adds that early in the development of most mammals, when a female embryo has only about 1,000 cells, each cell makes a “decision” to inactivate one of the two X chromosomes, a process that silences most of the genes on that chromosome. The choice of which X chromosome to inactivate appears to be random, but when those cells divide, their descendants maintain that initial decision.

In the new research, the Johns Hopkins team mated female mice carrying two copies of the gene for green fluorescent protein — one on each of the two X chromosomes — with male mice whose single X chromosome carried the gene for a red fluorescent protein. The female offspring from this mating had cells that glowed red or green based on which X chromosome was silenced. Additionally, the team engineered the mice so that not all of their cells were color-coded, since that would make it hard to distinguish one cell from another. Instead, they designed a system that allowed a single cell type in each mouse, such as heart muscle cells, to be color-coded. Their genetic trick resulted in red and green color maps with distinctive patterns for each cell and tissue type that they examined.

Nathans explains that the patterns are determined by the way each tissue develops. Some tissues are created from a very small number of “founder cells” in the early embryo; others are created from a large number. Statistically, the larger the group of founder cells, the greater the chances are of having a nearly equivalent number of red and green cells. Although the ratio in the founding group is roughly preserved as the tissue grows, the distribution of those cells is determined by how much movement occurs during the development of the tissue. For example, in a tissue like blood, where the cells move a lot, the red and green cells are finely intermingled. By contrast, in skin, where the cells show little movement, each patch of skin consists of the descendants of a single cell, which share the same inactive X chromosome — and therefore the same color — creating a coarse patchwork of red and green.

Normally, the pattern of X chromosome inactivation is not easily visualized. This color-coding technique is likely to be valuable for many studies, Nathans says, especially for research on variations caused by changes in the DNA sequence of the X chromosome, referred to as X-linked variation.  X-linked genetic variations, such as hemophilia or color blindness, are relatively common, in part because the X chromosome carries many genes — approximately 1,000, or close to 4 percent of the total.

Males who inherit an X-linked disease usually suffer its effects because they have no second X chromosome to compensate for the mutant version of the gene. Female relatives, on the other hand, are more typically “carriers” of X-linked diseases. They have the ability to pass the disease along to their male progeny, but they do not suffer from it themselves due to the normal copy of the gene on their second X chromosome.

In the tissues of certain carrier females, however, the cells that have silenced the X chromosome with a mutated gene cannot compensate for the defect in the cells that have silenced the X chromosome with the normal gene. Nathans and his team saw such a pattern when they examined the retinas of mice that were carriers for mutations in the Norrie disease gene, which is located on the X chromosome. The Norrie disease gene codes for a protein, Norrin, which controls blood vessel formation in the retina. Women who are carriers for Norrie disease can have defects in their retinas, but some women are more affected than others, and sometimes one eye is more affected than the other eye in the same individual.

The team found that in female mice that were Norrie disease carriers, variation in blood vessel structure corresponded to localized variations in X chromosome inactivation. When the X chromosome carrying the normal copy of the Norrie disease gene was silenced in a group of cells, the blood vessels nearby failed to form properly. In contrast, when the X chromosome carrying the mutated copy of the Norrie disease gene was silenced, the nearby blood vessels developed normally.

“X chromosome inactivation is a fascinating aspect of mammalian biology,” says Nathans. “This new technique for visualizing the pattern of X chromosome inactivation should be particularly useful for looking at the role that this process plays in brain development, including the ways that it contributes to differences between the left and right sides of the female brain, and to differences in brain structure between males and females and among different females, including identical twins.”

The research, published today in the journal Cell Metabolism, provides further insights on how the insulin-producing beta cells are formed in the pancreas. The team discovered that mutations in two specific genes which are important for development of the pancreas can cause the disease. These findings increase the number of known genetic causes of neonatal diabetes to 20. The study was funded by the Wellcome Trust, Diabetes UK, European Community’s Seventh Framework Programme, with some of the authors supported by the National Institute for Health Research (NIHR).

Dr Sarah Flanagan, lead author on the paper, said: “We are very proud to be able to give answers to the families involved on why their child has diabetes. Neonatal diabetes is diagnosed when a child is less than six months old, and some of these patients have added complications such as muscle weakness and learning difficulties with or without epilepsy.

“Our genetic discovery is critical to the advancement of knowledge on how insulin-producing beta cells are formed in the pancreas, which has implications for research into manipulating stem cells, which could one day lead to a cure.”

Dr Alasdair Rankin, Diabetes UK  Director of Research, said: “As well as shedding further light on the genetic causes of neonatal diabetes and providing answers for parents of children with this rare condition, this work helps us understand how the pancreas develops. Many people with diabetes can no longer make insulin and would benefit from therapies that replace the insulin producing beta cells of the pancreas. The results of this study are critical to bringing the day closer when this type of treatment is possible.”

Neonatal diabetes is caused by a change in a gene which affects insulin production. This means that levels of blood glucose (sugar) in the body rise dangerously high.

The Exeter team is the leading centre for neonatal diabetes having recruited over 1200 patients from more than 80 countries. This specific study focussed on 147 young people with neonatal diabetes, a rare condition which affects approximately 1 in 100,000 births. Following a systematic screen, 110 patients received a genetic diagnosis. For the remaining 37 patients, mutations in genes important for human pancreatic development were screened. Mutations were found in 11 patients, four of which were in one of two genes not previously known to cause neonatal diabetes (NKX2-2 and MNX1).

For many of the 121 (82%) patients who received a genetic diagnosis, knowing the cause of the diabetes will result in improved treatment, and for all the patients it will provide important information on risk of neonatal diabetes in future pregnancies. These patients also provide important scientific insights into pancreatic development.

Although drugs have been developed that inhibit the imbalance of neurotransmitters in the brain – a condition which causes many brain disorders and nervous system diseases – the exact understanding of the mechanism by which these drugs work has not yet been fully explained.

Now, researchers at the Hebrew University of Jerusalem, using baker’s yeast as a model, have deciphered the mode by which the inhibitors affect the neurological transmission process and have even been able to manipulate it.

Their work, reported in a recent article in the Journal of Biological Chemistry, raises hopes that these insights could eventually guide clinical scientists to develop new and more effective drugs for brain disorders associated with neurotransmitter imbalance.

All of the basic tasks of our existence are executed by the brain – whether it is breathing, heartbeat, memory building or physical movements – which depend on the highly regulated and efficient release of neurotransmitters – chemicals that act as messengers enabling extremely rapid connections between the neurons in the brain.

When even one part of the everyday “conversation” between neighboring neurons breaks down, the results can be devastating. Many brain disorders and nervous system diseases, including Huntington’s disease, various motor dysfunctions and even Parkinson’s disease, have been linked to problems with neurotransmitter transport.

The neurotransmitters are stored in the neuron in small, bubble-like compartments, called vesicles, containing transport proteins that are responsible for the storage of the neurotransmitters into the vesicles.

The storage of certain neurotransmitters is controlled by what is called the vesicular monoamine transporter (VMAT), which is known to transport a variety of vital neurotransmitters, such as adrenaline, dopamine and serotonin.

In addition, it can also transport the detrimental MPP+, a neurotoxin involved in models of Parkinson’s disease.

A number of studies demonstrated the significance of VMAT as a target for drug therapy in a variety of pathologic states, such as high blood pressure, hyperkinetic movement disorders and Tourette syndrome.

Many of the drugs that target VMAT act as inhibitors, including the classical VMAT2 inhibitor, tetrabenazine. Tetrabenazine has long been used for the treatment of motor dysfunctions associated with Huntington’s disease and other movement disorders. However, the mechanism by which the drug affects the storage of neurotransmitters was not fully understood.

The Hebrew University study set out, therefore, to achieve an understanding of the basic biochemical mechanism underlying the VMAT reaction, with a view towards better controlling it through new drug designs.

The research was conducted by in the laboratory of Prof. Shimon Schuldiner of the Hebrew University’s Department of Biological Chemistry; Dr.Yelena Ugolev, postdoctoral fellow in the laboratory; and research students Tali Segal, Dana Yaffe and Yael Gros.

To identify protein sequences responsible for tetrabenazine binding, the Hebrew University scientists harnessed the power of yeast genetics along with the method of directed evolution.

Expressing the human protein VMAT in baker’s yeast cells confers them with the ability to grow in the presence of toxic substrates, such as neurotoxin MPP+. Directed evolution mimics natural evolution in the laboratory and is a method used in protein engineering.

By using rounds of random mutations targeted to the gene encoding the protein of interest, the proteins can be tuned to acquire new properties or to adapt to new functions or environment.

The study led to identification of important flexible domains (or regions) in the structure of the VMAT, responsible for producing optional rearrangements in tetrabenazine binding, and also enabling regulation of the velocity of the neurotransmitter transporter.

Utilizing these new, controllable adaptations could serve as a guide for clinical scientists to develop more efficient drugs for brain disorders associated with neurotransmitter imbalance, say the Hebrew University researchers.