Neuroscience
Month
Researchers from McGill University and the University of Montreal have identified a crucial link between protein synthesis and autism spectrum disorders (ASD), which can bolster new therapeutic avenues. Regulation of protein synthesis, also termed mRNA translation, is the process by which cells manufacture proteins.
Autism spectrum disorders (ASD) encompass a wide array of neurodevelopmental diseases that affect three areas of behaviour: social interactions, communication and repetitive interests or behaviors. According to the U.S.-based Centers for Disease Control and Prevention, 1 in 88 children suffer from ASD, and the disorder is reported to occur in all racial, ethnic, and socioeconomic groups. ASDs are almost five times more common among boys (1 in 54) than among girls (1 in 252).
“My lab is dedicated to elucidating the role of dysregulated protein synthesis in cancer etiology. However, our team was surprised to discover that similar mechanisms may be implicated in the development of ASD”, explained Prof. Nahum Sonenberg, from McGill’s Dept. of Biochemistry, Faculty of Medicine, and the Goodman Cancer Research Centre. “We used a mouse model in which a key gene controlling initiation of protein synthesis was deleted. In these mice, production of neuroligins was increased. Neuroligins are important for the formation and regulation of connections known as synapses between neuronal cells in the brain and essential for the maintenance of the balance in the transmission of information from neuron to neuron.”
“Since the discovery of neuroligin mutations in individuals with ASD in 2003, the precise molecular mechanisms implicated remain unknown,” said Christos Gkogkas, a postdoctoral fellow at McGill and lead author. “Our work is the first to link translational control of neuroligins with altered synaptic function and autism-like behaviors in mice. The key is that we achieved reversal of ASD-like symptoms in adult mice. Firstly, we used compounds, which were previously developed for cancer treatment, to reduce protein synthesis. Secondly, we used non-replicating viruses as vehicles to put a break on exaggerated synthesis of neuroligins.”
Computer modeling played an important role in this research. “By using a new sophisticated computer algorithm that we specially developed to answer Dr. Sonenberg’s questions, we identified the unique structures of mRNAs of the neuroligins that could be responsible for their specific regulation,” explained Prof. François Major, of the University of Montreal’s Institute for Research in Immunology and Cancer and Department of Computer Science.
The researchers found that dysregulated synthesis of neuroligins augments synaptic activity, resulting in an imbalance between excitation and inhibition in single brain cells, opening up exciting new avenues for research that may unlock the secrets of autism.
“The autistic behaviours in mice were prevented by selectively reducing the synthesis of one type of neuroligin and reversing the changes in synaptic excitation in cells,” explained Prof. Jean-Claude Lacaille at the University of Montreal’s Groupe de Recherche sur le Système Nerveux Central and Department of Physiology. “In short, we manipulated mechanisms in brain cells and observed how they influence the behaviour of the animal.” The researchers were also able to reverse changes in inhibition and augment autistic behaviors by manipulating a second neuroligin. “The fact that the balance can be affected suggests that there could be a potential for pharmacological intervention by targeting these mechanisms,” Lacaille concluded.
MRI shows changes in the brains of people with post-concussion syndrome (PCS), according to a new study published online in the journal Radiology. Researchers hope the results point the way to improved detection and treatment for the disorder.
PCS affects approximately 20 percent to 30 percent of people who suffer mild traumatic brain injury (MTBI)—defined by the World Health Organization as a traumatic event causing brief loss of consciousness and/or transient memory dysfunction or disorientation. Symptoms of PCS include headache, poor concentration and memory difficulty.
Conventional neuroimaging cannot distinguish which MTBI patients will develop PCS.
"Conventional imaging with CT or MRI is pretty much normal in MTBI patients, even though some go on to develop symptoms, including severe cognitive problems," said Yulin Ge, M.D., associate professor, Department of Radiology at the NYU School of Medicine in New York City. "We want to try to better understand why and how these symptoms arise."
Dr. Ge’s study used MRI to look at the brain during its resting state, or the state when it is not engaged in a specific task, such as when the mind wanders or while daydreaming. The resting state is thought to involve connections among a number of regions, with the default mode network (DMN) playing a particularly important role.
"Baseline DMN is very important for information processing and maintenance," Dr. Ge said.
Alterations in DMN have been found in several psychiatric disorders, including Alzheimer’s disease, autism and schizophrenia, but little is known about DMN connectivity changes in MTBI.
For the new study, Dr. Ge and colleagues used resting-state functional MRI to compare 23 MTBI patients who had post-traumatic symptoms within two months of the injury and 18 age-matched healthy controls. Resting state MRI detects distinct changes in baseline oxygen level fluctuations associated with brain functional networks between patients with MTBI and control patients.
The MRI results showed that communication and information integration in the brain were disrupted among key DMN structures after mild head injury, and that the brain tapped into different neural resources to compensate for the impaired function.
"We found decreased functional connectivity in the posterior network of the brain and increased connectivity in the anterior component, probably due to functional compensation in patients with PCS," Dr. Ge said. "The reduced posterior connectivity correlated positively with neurocognitive dysfunction."
Dr. Ge and the other researchers hope to recruit additional MTBI patients for further studies with an eye toward developing a biomarker to monitor disease progression and recovery as well as treatment effects.
"We want to do studies to look at the changes in the network over time and correlate these functional changes with structural changes in the brain," he said. "This could give us hints on treatments to bring back cognitive function."
Scientists at the Mainz University Medical Center have discovered another molecule that plays an important role in regulating myelin formation in the central nervous system. Myelin promotes the conduction of nerve cell impulses by forming a sheath around their projections, the so-called axons, at specific locations – acting like the plastic insulation around a power cord. The research team, led by Dr. Robin White of the Institute of Physiology and Pathophysiology at the University Medical Center of Johannes Gutenberg University Mainz, recently published their findings in the prestigious journal EMBO reports.
Complex organisms have evolved a technique known as saltatory conduction of impulses to enable nerve cells to transmit information over large distances more efficiently. This is possible because the specialized nerve cell axonal projections involved in conducting impulses are coated at specific intervals with myelin, which acts as an insulating layer. In the central nervous system, myelin develops when oligodendrocytes, which are a type of brain cell, repeatedly wrap their cellular processes around the axons of nerve cells forming a compact stack of cell membranes, a so-called myelin sheath. A myelin sheath not only has a high lipid content but also contains two main proteins, the synthesis of which needs to be carefully regulated.
The current study analyzed the synthesis of myelin basic protein (MBP), a substance which is essential for the formation and stabilization of myelin membranes. In common with all proteins, MBP is generated in a two-stage process originating from basic genetic material in the form of DNA. First, DNA is converted to mRNA, which, in turn, serves as a template for the actual synthesis of MBP. During myelin formation, the synthesis of MBP in oligodendrocytes is suppressed until distinct signals from nerve cells initiate myelination at specific “production sites”. To date, the mechanisms involved in the suppression of MBP synthesis over relatively long periods of time have not been understood. This is where the current work of the Mainz scientists comes in, as they were able to identify a molecule that is responsible for the suppression of MBP synthesis.
"This molecule, called sncRNA715, binds to MBP mRNA, thus preventing MBP synthesis," explains Dr. Robin White. "Our research findings show that levels of sncRNA715 and MBP inversely correlate during myelin formation and that it is possible to influence the extent of MBP production in oligodendrocytes by artificially modifying levels of sncRNA715. This indicates that the recently discovered molecule is a significant factor in the regulation of MBP synthesis."
Understanding the molecular basis for myelin formation is essential with regard to various neurological illnesses that involve a loss of the protective myelin layer. For example, it is still unclear why oligodendrocytes lose their ability to repair the damage to myelin in the progress of multiple sclerosis (MS). “Interestingly, in collaboration with our Dutch colleagues, we have been able to identify a correlation between levels of sncRNA715 and MBP in the brain tissue of MS patients,” Robin White continues. “In contrast with unaffected areas of the brain in which the myelin structure appears normal, there are higher levels of sncRNA715 in affected areas in which myelin formation is impaired. Our findings may help to provide a molecular explanation for myelination failures in illnesses such as multiple sclerosis.”
The discovery of the molecular pathway that drives the changes seen in the brains of Alzheimer’s patients is reported today, revealing new targets for drug discovery that could be exploited to combat the disease. The study gives the most detailed understanding yet of the complex processes leading to Alzheimer’s.
Alzheimer’s disease is associated with plaques made up of deposits of a molecule called amyloid between brain cells, which leads to the formation of tangles of twisted fibres made from a molecule called tau, found inside the brain cells. This causes the death of brain cells which is thought to bring about the symptoms of memory loss and dementia. Although it has been accepted for over twenty years that the progression of disease is driven by amyloid and results in abnormal changes in tau, the exact mechanisms of disease remain somewhat of a mystery.
Recent genome wide association studies have identified the gene for a molecule called clusterin as a susceptibility factor for late-onset Alzheimer’s disease. Levels of clusterin are also known to be elevated in blood in patients with Alzheimer’s from an early stage in the disease so the researchers wanted to find out what role it might play in the progression of disease.
The team, led by researchers at King’s College London’s Institute of Psychiatry, looked first in mouse brain cells grown in the laboratory and found that the presence of amyloid alters the amount of clusterin in these cells. Clusterin then acts to switch on a signalling pathway that drives the changes in tau that are associated with the formation of tangles inside the cells, another hallmark of the disease. When this signalling pathway was chronically switched on in a mouse model of the disease, the researchers observed an increase in tangle formation and evidence of cognitive defects.
The study, published in the journal Molecular Psychiatry, also looked in humans and detected the signature of clusterin activation in the brains of Alzheimer’s patients but not in the brains of patients with other forms of dementia.
Dr Richard Killick from King’s College London’s Institute of Psychiatry said: “This is the first time we’ve been able to connect the molecular mechanisms behind the formation of amyloid plaques in the brain with the formation of tangles inside the brain cells, two of the defining features of Alzheimer’s disease. Our research has given the most detailed picture yet of how the disease progresses and we hope it will offer leads for the development of new treatments.”
The signalling pathway that is turned on by clusterin is called DKK1-WNT. It involves interactions between a number of different molecules that could prove to be useful targets for the development of new drugs.
Current treatments for Alzheimer’s are focused on alleviating the symptoms and there is no therapy that can prevent the progression of disease.
Professor Simon Lovestone, also from King’s College London’s Institute of Psychiatry, who led the study, said: “We have shown that we can block the toxic effects of amyloid when we stop this signalling pathway in brain cells grown in the lab. We believe that if we could block its activity in the brains of Alzheimer’s patients too, we may have an opportunity to halt the disease in man. Indeed, we have already begun our own drug development programme to do just that and are at the stage where potential compounds are coming back to us for further testing.”
The DKK1-WNT pathways has also been implicated in some human cancers and although there is no evidence for a direct link, the findings from this study mean that there could be an opportunity to make advances in Alzheimer’s research by capitalising on knowledge that is being gained from cancer research, the authors suggest.
Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, which helped fund this study, said: “We will see more and more people affected by Alzheimer’s disease as our population ages. This study gives us a much-needed additional insight to the complex biology that contributes to the development of Alzheimer’s, which is vital if we are to develop new treatments that are so urgently needed.”
Health professionals may soon have a new method of diagnosing Parkinson’s disease, one that is noninvasive and inexpensive, and, in early testing, has proved to be effective more than 90 percent of the time.
In addition, this new method has the potential to track the progression of Parkinson’s, as well as measure the effectiveness of treatments for the disorder, said Rahul Shrivastav, professor and chairperson of Michigan State University’s Department of Communicative Sciences and Disorders and a member of the team developing the new method.
It involves monitoring a patient’s speech patterns – specifically, movement patterns of the tongue and jaw.
“In Parkinson’s disease, a common limitation is that the movements become slow and have a reduced range,” said Shrivastav. “We believe we see this pattern in speech too – the tongue doesn’t move as far as it should, doesn’t move as quickly as it should and produces subtle changes in speech patterns.”
This method is particularly sensitive to Parkinson’s disease speech and, Shrivastav said, is effective with only two seconds of speech.
“That’s significant in several ways: The detection methodology is noninvasive, easy to administer, inexpensive and capable of being used remotely and in telemedicine applications,” he said.
Presently there are no tried-and-true methods for diagnosing Parkinson’s. Shrivastav said if a person is showing early symptoms of the disease, which include tremors, slower movements or rigid muscles, he or she is given a drug to treat the disease.
“If the symptoms go away,” he said, “then it’s assumed you must have Parkinson’s disease.”
In more advanced cases, he said, symptoms are usually prominent enough that it is fairly easy to diagnose.
Parkinson’s disease is a neurological disorder affecting a half million people in the United States, with 50,000 newly diagnosed cases every year. It occurs when nerve cells in the brain stop producing a chemical called dopamine, which helps control muscle movement. Without dopamine, the nerve cells cannot properly send messages, leading to the loss of muscle function.
While there is no cure for Parkinson’s disease, early detection is particularly important since the treatments currently available for controlling symptoms are most effective at that stage.
A new study published November 20 in the open-access journal PLOS Biology has identified hundreds of small regions of the genome that appear to be uniquely regulated in human neurons. These regulatory differences distinguish us from other primates, including monkeys and apes, and as neurons are at the core of our unique cognitive abilities, these features may ultimately hold the key to our intellectual prowess (and also to our potential vulnerability to a wide range of ‘human-specific’ diseases from autism to Alzheimer’s).
Exploring which features in the genome separate human neurons from their non-human counterparts has been a challenging task until recently; primate genomes comprise billions of base pairs (the basic building blocks of DNA), and comparisons between the human and chimpanzee genomes alone reveal close to 40 million differences. Most of these are thought to merely reflect random ‘genetic drift’ during the course of evolution, so the challenge was to identify the small set of changes that have functionally important consequences, as these might help to explain the genomic basis of the emergence of human-specific neuronal function.
The key to the present study, led by Dr Schahram Akbarian of the University of Massachusetts and the Mount Sinai School of Medicine, was not to focus on the “letters” of the DNA code, but rather on what might be called its “font” or “typeface”—the DNA strands of the genome are wrapped in protein to make a chromatin fiber, and the way in which they are wrapped, the “chromatin state”, in turn reflects the regulatory state of that region of the genome (e.g. whether a given gene is turned on or off). This is the field that biologists call “epigenetics”—the study of the “epigenome”.
Dr Akbarian and colleagues set out to isolate small snippets of chromatin fibers from the frontal cortex, a brain region involved in complex cognitive operations. They were then able to analyze these snippets for the chemical signals (histone methylation) that define the regulatory state (on/off) of the chromatin. The results of their analysis identified hundreds of regions throughout the genome which showed a markedly different chromatin structure in neurons from human children and adults, compared to chimpanzees and macaques.
This treasure trove of short genomic regions is now providing researchers with interesting new leads involving the evolution of the human brain. Although some of the regions have remained unchanged during primate evolution, some more tantalizing ones have recently changed, having a DNA sequence that is unique to humans and our close extinct relatives, the Neanderthals and the Denisovans.
The study also uncovered examples where several of these regulatory DNA regions appear to physically interact with each other inside the cell nucleus, despite being separated by hundreds of thousands of base pairs on the linear genome. This phenomenon of “chromatin looping” is implicated in controlling the expression of neighboring genes, including several with a critical role for human brain development. The study, from laboratories based in the United States, Switzerland and Russia, draws further attention to the role of epigenetics and the epigenome in our biology and our evolution. As Dr Akbarian notes, “Much about human biology and disease cannot be deduced by simply sequencing the genome. Mapping the epigenome of neurons and other cells will help us to better understand the inner workings of our brain, and where we are coming from.”
A novel test that measures proteins from nerve damage that are deposited in blood and spinal fluid reveals the rate of progression of amyotrophic lateral sclerosis (ALS) in patients, according to researchers from Mayo Clinic’s campus in Florida, Emory University and the University of Florida.
Their study, which appears online in the Journal of Neurology, Neurosurgery & Psychiatry, suggests this test, if perfected, could help physicians and researchers identify those patients at most risk for rapid progression. These patients could then be offered new therapies now being developed or tested.
ALS — also known as Lou Gehrig’s disease — is a progressive neurodegenerative disease caused by deterioration of motor neurons (nerve cells) that control voluntary muscle movement. The rate of progression varies widely among patients, and survival from the date of diagnosis can be months to 10 years or more, says Kevin Boylan, M.D., medical director of the ALS Clinic at Mayo Clinic in Florida.
"In the care of our ALS patients there is a need for more reliable ways to determine how fast the disease is progressing," says Dr. Boylan, who is the study’s lead investigator. "Many ALS researchers have been trying to develop a molecular biomarker test for nerve damage like this, and we are encouraged that this test shows such promise. Because blood samples are more readily collected than spinal fluid, we are especially interested in further evaluating this test in peripheral blood in comparison to spinal fluid."
There are no curative or even significantly beneficial therapies in clinics now for ALS treatment, but many are in development, Dr. Boylan says. A test like this could help identify those patients who are at risk for faster progression of weakness. With experimental treatments that primarily slow progression of ALS, detecting a treatment response in patients with faster progression may be easier to detect, says Dr. Boylan. Now, patients with varying rates of progression participate together in clinical studies, which can make analysis of a drug’s benefit difficult, he says.
"If there were a way to identify people who are likely to have relatively faster progression, it should be possible to conduct therapeutic trials with smaller numbers of patients in less time than is required presently," Dr. Boylan says.
A longer-range goal is to develop tests of this kind to gauge how well a patient is responding to experimental therapies, he adds.
The test measures neurofilament heavy form in blood and spinal fluid. These are proteins that provide structure to motor neurons, and when these nerves are damaged by the disease, the proteins break down and float free in blood serum and in the spinal fluid. Earlier research in this area was conducted by Gerry Shaw, Ph.D., a neuroscientist at the University of Florida, who is the study’s senior investigator and the developer of the neurofilament assay used in the study.
The researchers measured neurofilament heavy form in blood and spinal fluid samples from patients at Mayo Clinic and at Emory University, and correlated levels of the protein with rate of progression. “We demonstrated a solid association between higher levels of this protein and a faster progression of muscle weakness,” Dr. Boylan says. There was also evidence suggesting that ALS patients with higher protein levels may have shorter survival, he adds.
Deciphering what causes the brain cell degeneration of Parkinson’s disease has remained a perplexing challenge for scientists. But a team led by scientists from The Scripps Research Institute (TSRI) has pinpointed a key factor controlling damage to brain cells in a mouse model of Parkinson’s disease. The discovery could lead to new targets for Parkinson’s that may be useful in preventing the actual condition.
The team, led by TSRI neuroscientist Bruno Conti, describes the work in a paper published online ahead of print on November 19, 2012 by the Journal of Immunology.
Parkinson’s disease plagues about one percent of people over 60 years old, as well as some younger patients. The disease is characterized by the loss of dopamine-producing neurons primarily in the substantia nigra pars compacta, a region of the brain regulating movements and coordination.
Among the known causes of Parkinson’s disease are several genes and some toxins. However, the majority of Parkinson’s disease cases remain of unknown origin, leading researchers to believe the disease may result from a combination of genetics and environmental factors.
Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson’s, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now.
Researchers at McMaster University have discovered new genetic evidence about why some people are happier than others.
McMaster scientists have uncovered evidence that the gene FTO – the major genetic contributor to obesity – is associated with an eight per cent reduction in the risk of depression. In other words, it’s not just an obesity gene but a “happy gene” as well.
The research appears in a study published in the journal Molecular Psychiatry. The paper was produced by senior author David Meyre, associate professor in clinical epidemiology and biostatistics at the Michael G. DeGroote School of Medicine and a Canada Research Chair in genetic epidemiology; first author Dr. Zena Samaan, assistant professor, Department of Psychiatry and Behavioural Neurosciences, and members of the Population Health Research Institute of McMaster University and Hamilton Health Sciences.
“The difference of eight per cent is modest and it won’t make a big difference in the day-to-day care of patients,” Meyre said. “But, we have discovered a novel molecular basis for depression.”
In the past, family studies on twins, and brothers and sisters, have shown a 40 per cent genetic component in depression. However, scientific studies attempting to associate genes with depression have been “surprisingly unsuccessful” and produced no convincing evidence so far, Samaan said.
The McMaster discovery challenges the common perception of a reciprocal link between depression and obesity: That obese people become depressed because of their appearance and social and economic discrimination; depressed individuals may lead less active lifestyles and change eating habits to cope with depression that causes them to become obese.
“We set out to follow a different path, starting from the hypothesis that both depression and obesity deal with brain activity. We hypothesized that obesity genes may be linked to depression,” Meyre said.
The McMaster researchers investigated the genetic and psychiatric status of patients enrolled in the EpiDREAM study led by the Population Health Research Institute, which analyzed 17,200 DNA samples from participants in 21 countries.
In these patients, they found the previously identified obesity predisposing genetic variant in FTO was associated with an eight per cent reduction in the risk of depression. They confirmed this finding by analyzing the genetic status of patients in three additional large international studies.
Meyre said the fact the obesity gene’s same protective trend on depression was found in four different studies supports their conclusion. It is the “first evidence” that an FTO obesity gene is associated with protection against major depression, independent of its effect on body mass index, he said.
This is an important discovery as depression is a common disease that affects up to one in five Canadians, said Samaan.
Schizophrenia wrecks the lives of millions worldwide – and has defeated researchers looking for a single cause. Time for complex new thinking.
PAUL is 21. He thinks the voices started a couple of years ago, but it’s hard to remember exactly because they just seemed to fade in. They whisper insistently, commenting on his actions, trying to control his thoughts and feelings. Living with them is a constant battle, causing him to drop out of college and stop seeing friends. He has been treated in hospital and is being prescribed antipsychotic drugs, but he sees all this as part of a conspiracy.
Paul’s world view is informed by psychosis. This mental state disrupts perception and the interpretation of reality, and is characterised by hallucinations and delusions. Doctors recognise psychosis as a marker for many medical conditions ranging from those caused by electrolyte disturbance to epilepsy, dementia and rare autoimmune disorders.
In Paul’s case these conditions are rapidly excluded. After other short-lived, mood or drug-related causes are also excluded, Paul is diagnosed with schizophrenia - one of a group of disorders characterised by psychosis. But schizophrenia also affects Paul’s emotional and verbal responsiveness, motivation and insight. And it is these functional symptoms that are its most disabling features because they erode the ability to interact with others, maintain social contacts and work.
So what is schizophrenia? In the late 19th century German psychiatrist Emil Kraepelin identified the symptoms and presentation of a disease later called schizophrenia by Eugen Bleuler, a Swiss psychiatrist. Bleuler saw it as an umbrella term for a collection of diseases. Despite attempts to define subtypes or identify specific forms, schizophrenia is still treated broadly as a single disease, and it affects around 1 per cent of adults.
So a shorter, more honest answer to the question of what schizophrenia is would be that we won’t really know until we can define its neurobiological basis. For now, psychosis represents a major frontier in neuroscience because it shakes our certainties about the way we see the world - and understand the brain.