Neuroscience
Month
The effect that genes have on our brain depends on our age. These are the findings of a group of researchers from the MedUni Vienna. It has been known for a number of years that particular genetic variations are of importance for the functioning of neural circuits in the brain. Just how these effects differ in the various stages of life has until recently not been fully understood. This international study has been able to demonstrate that genetic variations at different times in our lives can actually have opposite effects on the brain, which provides an explanation for the differences that clinicians observe in the psychiatric symptoms and response to medications of adolescents and adults.
The group of researchers from Vienna, in collaboration with international cooperation partners, has shown that the effect of a psychiatric risk gene on a resting state network in the forebrain depends greatly on the patient’s age.
The human forebrain is crucial for planning and action, which are closely interwoven with concentration, attention and memory functions. The nerve transmitter substance dopamine orchestrates the activity of neurons in the forebrain in order to ensure an ideal level of functioning. The amount of dopamine in the brain is not constant for life, however. Instead, it rises until adolescence and then falls by the time the individual reaches early adulthood to a much lower level. When the dopaminergic control function collapses, serious mental illnesses such as schizophrenia, depression or attention deficit / hyperactivity disorder (ADHD) can result that usually start around the period of transition to adulthood.
For a number of years, doctors have known that a risk gene involved in dopamine metabolism (COMT) can affect neuronal regulation of the forebrain in adults. Carriers of risk gene variants are more prone to dopaminergic mental illness.
The interaction of genes and stages of development
As part of the study, carried out at the MedUni Vienna’s University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team used magnetic resonance imaging data from a large random sample of over 200 test subjects to analyse the complex interaction between stages of development and genetic variations in the COMT gene and how it affects the resting state network of the forebrain.
Some of the magnetic resonance scans were performed in Vienna (Centre of Excellent, High-Field MR, Department of MR Physics, Head: Ewald Moser) and some as part of an EU project (Institute of Psychiatry, London, Head: Gunther Schumann). Gene analyses (COMT Val158Met) were carried out in Vienna (Univ. Dept. of Laboratory Medicine, Harald Esterbauer and colleagues) or as part of the EU project.
"Our age has a crucial influence on the effects of psychiatric risk genes. A gene that has positive effects during puberty can be bad for us in adulthood," says study leader Lukas Pezawas, describing the results. In the study, adolescents exhibited contrary gene effects on the brain compared to adults.
The study highlights the dynamism of gene effects on brain function throughout the various stages of life such as adolescence or adulthood. “These results are important for understanding the onset of illness in conditions such as schizophrenia, depression or ADHD, which mostly occur at the threshold of adulthood. Our results also show that there are fundamental differences in the dopamine system between adolescents and adults, which we need to take into account in future treatments”, explains Pezawas.
Future prevention and treatment strategies for vascular diseases may lie in the evaluation of early brain imaging tests long before heart attacks or strokes occur, according to a systematic review conducted by a team of cardiologists, neuroscientists, and psychiatrists from Icahn School of Medicine at Mount Sinai and published in the October issue of JACC Cardiovascular Imaging.
For the review, Mount Sinai researchers examined all relevant brain imaging studies conducted over the last 33 years. They looked at studies that used every available brain imaging modality in patients with vascular disease risk factors but no symptoms that would lead to a diagnosis of diseased blood vessels (vascular disease) in the heart or brain, or periphery (e.g. arms and legs).
The review demonstrates that patients with high blood pressure, diabetes, obesity, high cholesterol, smoking, or metabolic syndrome, but no symptoms, still had visible signs on their neuroimaging scans of structural and functional brain changes long before the development of any events related to vascular diseases of the heart (heart attack) or brain (stroke).
"This is the first time we have been able to disentangle the brain effects of vascular disease risk factors from the brain effects of cardiovascular and cerebrovascular disease and/or events after they develop," says the article’s lead author, Joseph I. Friedman, MD, Associate Professor in the Departments of Psychiatry and Neuroscience at Icahn School of Medicine at Mount Sinai. "Moreover, subtle cognitive impairment is an important clinical manifestation of these vascular disease risk factor-related brain imaging changes in these otherwise healthy persons."
Dr. Friedman added that, because diminished cognitive capacity adversely impacts a person’s ability to benefit from treatment for these medical conditions, early identification of these brain changes may “present a new window of opportunity” for doctors to intervene early and improve prevention of advancement from vascular disease risk factors to established cardiovascular and cerebrovascular diseases. His team is currently testing these hypotheses in ongoing studies at Mount Sinai.
"Patients need to start today to control their vascular risk factors, otherwise their brains may forever harbor physical changes leading to devastating heart and vascular conditions impacting their future overall health and even cognitive decline causing diseases like dementia or when it exists it can accelerate Alzheimer’s," says study author, Valentin Fuster, MD, PhD, Director of Mount Sinai Heart, Physician-in-Chief of The Mount Sinai Hospital, and Chief of the Division of Cardiology at Icahn School of Medicine at Mount Sinai. "Our publication raises the possibility that these early brain changes are major warning signs of what the future may hold for these asymptomatic patients. These high risk patients, along with their doctors, hold the power to modify their daily vascular risk factors to help halt the future course of the manifestation of their potentially looming cardiovascular diseases."
"We hope our publication serves as a primer for cardiologists and other doctors interpreting the early neuroimaging data of their patients who may be high risk for vascular disease," says senior article author Jagat Narula, MD, PhD, Director of Cardiovascular Imaging, Professor of Medicine and Philip J. and Harriet L. Goodhart Chair in Cardiology at Icahn School of Medicine at Mount Sinai. "These subtle brain changes are clues to us physicians that our patients need to start to lower their vascular risk factors always and way before symptoms or a cardiac or brain event happens. This simple step to lower vascular risk factors can have huge impacts on global prevention efforts of cardiovascular diseases."
Researchers identified the following impact of key vascular risk factors on the structural and functional brain health of asymptomatic patients:
Scientists have described a way to convert human skin cells directly into a specific type of brain cell affected by Huntington’s disease, an ultimately fatal neurodegenerative disorder. Unlike other techniques that turn one cell type into another, this new process does not pass through a stem cell phase, avoiding the production of multiple cell types, the study’s authors report.
(Image caption: Human skin cells (top) can be converted into medium spiny neurons (bottom) with exposure to the right combination of microRNAs and transcription factors, according to work by Andrew Yoo and his research team)
The researchers, at Washington University School of Medicine in St. Louis, demonstrated that these converted cells survived at least six months after injection into the brains of mice and behaved similarly to native cells in the brain.
“Not only did these transplanted cells survive in the mouse brain, they showed functional properties similar to those of native cells,” said senior author Andrew S. Yoo, PhD, assistant professor of developmental biology. “These cells are known to extend projections into certain brain regions. And we found the human transplanted cells also connected to these distant targets in the mouse brain. That’s a landmark point about this paper.”
The work appears Oct. 22 in the journal Neuron.
The investigators produced a specific type of brain cell called medium spiny neurons, which are important for controlling movement. They are the primary cells affected in Huntington’s disease, an inherited genetic disorder that causes involuntary muscle movements and cognitive decline usually beginning in middle-adulthood. Patients with the condition live about 20 years following the onset of symptoms, which steadily worsen over time.
The research involved adult human skin cells, rather than more commonly studied mouse cells or even human cells at an earlier stage of development. In regard to potential future therapies, the ability to convert adult human cells presents the possibility of using a patient’s own skin cells, which are easily accessible and won’t be rejected by the immune system.
To reprogram these cells, Yoo and his colleagues put the skin cells in an environment that closely mimics the environment of brain cells. They knew from past work that exposure to two small molecules of RNA, a close chemical cousin of DNA, could turn skin cells into a mix of different types of neurons.
In a skin cell, the DNA instructions for how to be a brain cell, or any other type of cell, is neatly packed away, unused. In past research published in Nature, Yoo and his colleagues showed that exposure to two microRNAs called miR-9 and miR-124 altered the machinery that governs packaging of DNA. Though the investigators still are unraveling the details of this complex process, these microRNAs appear to be opening up the tightly packaged sections of DNA important for brain cells, allowing expression of genes governing development and function of neurons.
Knowing exposure to these microRNAs alone could change skin cells into a mix of neurons, the researchers then started to fine tune the chemical signals, exposing the cells to additional molecules called transcription factors that they knew were present in the part of the brain where medium spiny neurons are common.
“We think that the microRNAs are really doing the heavy lifting,” said co-first author Matheus B. Victor, a graduate student in neuroscience. “They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors.”
Yoo also explained that the microRNAs, but not the transcription factors, are important components for the general reprogramming of human skin cells directly to neurons. His team, including co-first author Michelle C. Richner, senior research technician, showed that when the skin cells were exposed to the transcription factors alone, without the microRNAs, the conversion into neurons wasn’t successful.
The researchers performed extensive tests to demonstrate that these newly converted brain cells did indeed look and behave like native medium spiny neurons. The converted cells expressed genes specific to native human medium spiny neurons and did not express genes for other types of neurons. When transplanted into the mouse brain, the converted cells showed morphological and functional properties similar to native neurons.
To study the cellular properties associated with the disease, the investigators now are taking skin cells from patients with Huntington’s disease and reprogramming them into medium spiny neurons using the approach described in the new paper. They also plan to inject healthy reprogrammed human cells into mice with a model of Huntington’s disease to see if this has any effect on the symptoms.
A nano-sized discovery by Northwestern Medicine® scientists helps explain how bipolar disorder affects the brain and could one day lead to new drug therapies to treat the mental illness.
Scientists used a new super-resolution imaging method — the same method recognized with the 2014 Nobel Prize in chemistry — to peer deep into brain tissue from mice with bipolar-like behaviors. In the synapses (where communication between brain cells occurs), they discovered tiny “nanodomain” structures with concentrated levels of ANK3 — the gene most strongly associated with bipolar disorder risk. ANK3 is coding for the protein ankyrin-G.
“We knew that ankyrin-G played an important role in bipolar disease, but we didn’t know how,” said Northwestern Medicine scientist Peter Penzes, corresponding author of the paper. “Through this imaging method we found the gene formed in nanodomain structures in the synapses, and we determined that these structures control or regulate the behavior of synapses.”
Penzes is a professor in physiology and psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. The results were published Oct. 22 in the journal Neuron.
High-profile cases, including actress Catherine Zeta-Jones and politician Jesse Jackson, Jr., have brought attention to bipolar disorder. The illness causes unusual shifts in mood, energy, activity levels and the ability to carry out day-to-day tasks. About 3 percent of Americans experience bipolar disorder symptoms, and there is no cure.
Recent large-scale human genetic studies have shown that genes can contribute to disease risk along with stress and other environmental factors. However, how these risk genes affect the brain is not known.
This is the first time any psychiatric risk gene has been analyzed at such a detailed level of resolution. As explained in the paper, Penzes used the Nikon Structured Illumination Super-resolution Microscope to study a mouse model of bipolar disorder. The microscope realizes resolution of up to 115 nanometers. To put that size in perspective, a nanometer is one-tenth of a micron, and there are 25,400 microns in one inch. Very few of these microscopes exist worldwide.
“There is important information about genes and diseases that can only been seen at this level of resolution,” Penzes said. “We provide a neurobiological explanation of the function of the leading risk gene, and this might provide insight into the abnormalities in bipolar disorder.”
The biological framework presented in this paper could be used in human studies of bipolar disorder in the future, with the goal of developing therapeutic approaches to target these genes.
As you glance over a menu or peruse the shelves in a supermarket, you may be thinking about how each food will taste and whether it’s nutritious, or you may be trying to decide what you’re in the mood for. A new neuroimaging study suggests that while you’re thinking all these things, an internal calorie counter of sorts is also evaluating each food based on its caloric density.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
“Earlier studies found that children and adults tend to choose high-calorie food,” says study author Alain Dagher, neurologist at the Montreal Neurological Institute and Hospital. “The easy availability and low cost of high-calorie food has been blamed for the rise in obesity. Their consumption is largely governed by the anticipated effects of these foods, which are likely learned through experience.”
“Our study sought to determine how people’s awareness of caloric content influenced the brain areas known to be implicated in evaluating food options,” says Dagher. “We found that brain activity tracked the true caloric content of foods.”
For the study, 29 healthy participants were asked to examine pictures of 50 familiar foods. The participants rated how much they liked each food (on a scale from 1 to 20) and were asked to estimate the calorie content of each food. Surprisingly, they were poor at accurately judging the number of calories in the various foods, and yet, the amount participants were willing to bid on the food in a simulated auction matched up with the foods that actually had higher caloric content.
Results of functional brain scans acquired while participants looked at the food images showed that activity in the ventromedial prefrontal cortex, an area known to encode the value of stimuli and predict immediate consumption, was also correlated with the foods’ true caloric content.
Participants’ explicit ratings of how much they liked a food, on the other hand, were associated with activity in the insula, an area of the brain that has been linked to processing the sensory properties of food.
According to Dagher, understanding the reasons for people’s food choices could help to control the factors that lead to obesity, a condition that is linked to many health problems, including high blood pressure, heart disease, and Type 2 diabetes.
A drug being studied as a fast-acting mood-lifter restored pleasure-seeking behavior independent of – and ahead of – its other antidepressant effects, in a National Institutes of Health trial. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom – loss of interest in pleasurable activities – which lasted up to 14 days. Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain.
“Our findings help to deconstruct what has traditionally been lumped together as depression,” explained Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health. “We break out a component that responds uniquely to a treatment that works through different brain systems than conventional antidepressants – and link that response to different circuitry than other depression symptoms.”
This approach is consistent with the NIMH’s Research Domain Criteria project, which calls for the study of functions – such as the ability to seek out and experience rewards – and their related brain systems that may identify subgroups of patients in one or multiple disorder categories.
Zarate and colleagues reported on their findings Oct. 14, 2014 in the journal Translational Psychiatry.
Although it’s considered one of two cardinal symptoms of both depression and bipolar disorder, effective treatments have been lacking for loss of the ability to look forward to pleasurable activities, or anhedonia. Long used as an anesthetic and sometimes club drug , ketamine and its mechanism-of-action have lately been the focus of research into a potential new class of rapid-acting antidepressants that can lift mood within hours instead of weeks.
Based on their previous studies, NIMH researchers expected ketamine’s therapeutic action against anhedonia would be traceable – like that for other depression symptoms – to effects on a mid-brain area linked to reward-seeking and that it would follow a similar pattern and time course.
To find out, the researchers infused the drug or a placebo into 36 patients in the depressive phase of bipolar disorder. They then detected any resultant mood changes using rating scales for anhedonia and depression. By isolating scores on anhedonia items from scores on other depression symptom items, the researchers discovered that ketamine was triggering a strong anti-anhedonia effect sooner – and independent of – the other effects.
Levels of anhedonia plummeted within 40 minutes in patients who received ketamine, compared with those who received placebo – and the effect was still detectable in some patients two weeks later. Other depressive symptoms improved within 2 hours. The anti-anhedonic effect remained significant even in the absence of other antidepressant effects, suggesting a unique role for the drug.
Next, the researchers scanned a subset of the ketamine-infused patients, using positron emission tomography (PET), which shows what parts of the brain are active by tracing the destinations of radioactively-tagged glucose – the brain’s fuel. The scans showed that ketamine jump-started activity not in the middle brain area they had expected, but rather in the dorsal (upper) anterior cingulate cortex, near the front middle of the brain and putamen, deep in the right hemisphere.
Boosted activity in these areas may reflect increased motivation towards or ability to anticipate pleasurable experiences, according to the researchers. Depressed patients typically experience problems imagining positive, rewarding experiences – which would be consistent with impaired functioning of this dorsal anterior cingulate cortex circuitry, they said. However, confirmation of these imaging findings must await results of a similar NIMH ketamine trial nearing completion in patients with unipolar major depression.
Other evidence suggests that ketamine’s action in this circuitry is mediated by its effects on the brain’s major excitatory neurotransmitter, glutamate, and downstream effects on a key reward-related chemical messenger, dopamine. The findings add to mounting evidence in support of the antidepressant efficacy of targeting this neurochemical pathway. Ongoing research is exploring, for example, potentially more practical delivery methods for ketamine and related experimental antidepressants, such as a nasal spray .
However, ketamine is not approved by the U.S. Food and Drug Administration as a treatment for depression. It is mostly used in veterinary practice, and abuse can lead to hallucinations, delirium and amnesia.
A study led by University of Toronto psychology researchers has found that people who play action video games such as Call of Duty or Assassin’s Creed seem to learn a new sensorimotor skill more quickly than non-gamers do.
A new sensorimotor skill, such as learning to ride a bike or typing, often requires a new pattern of coordination between vision and motor movement. With such skills, an individual generally moves from novice performance, characterized by a low degree of coordination, to expert performance, marked by a high degree of coordination. As a result of successful sensorimotor learning, one comes to perform these tasks efficiently and perhaps even without consciously thinking about them.
“We wanted to understand if chronic video game playing has an effect on sensorimotor control, that is, the coordinated function of vision and hand movement,” said graduate student Davood Gozli, who led the study with supervisor Jay Pratt.
To find out, they set up two experiments. In the first, 18 gamers (those who played a first-person shooter game at least three times per week for at least two hours each time in the previous six months) and 18 non-gamers (who had little or no video game use in the past two years) performed a manual tracking task. Using a computer mouse, they were instructed to keep a small green square cursor at the centre of a white square moving target which moved in a very complicated pattern that repeated itself. The task probes sensorimotor control, because participants see the target movement and try to coordinate their hand movements with what they see.
In the early stages of doing the tasks, the gamers’ performance was not significantly better than non-gamers. “This suggests that while chronically playing action video games requires constant motor control, playing these games does not give gamers a reliable initial advantage in new and unfamiliar sensorimotor tasks,” said Gozli.
By the end of the experiment, all participants performed better as they learned the complex pattern of the target. The gamers, however, were significantly more accurate in following the repetitive motion than the non-gamers. “This is likely due to the gamers’ superior ability in learning a novel sensorimotor pattern, that is, their gaming experience enabled them to learn better than the non-gamers.”
In the next experiment, the researchers wanted to test whether the superior performance of the gamers was indeed a result of learning rather than simply having better sensorimotor control. To eliminate the learning component of the experiment, they required participants to again track a moving dot, but in this case the patterns of motion changed throughout the experiment. The result this time: neither the gamers nor the non-gamers improved as time went by, confirming that learning was playing a key role and the gamers were learning better.
One of the benefits of playing action games may be an enhanced ability to precisely learn the dynamics of new sensorimotor tasks. Such skills are key, for example, in laparoscopic surgery which involves high precision manual control of remote surgery tools through a computer interface.
A researcher at the University of Wisconsin-Milwaukee (UWM) has added to a growing body of evidence that links autism to air pollutants such as those generated by cars and trucks.
Amy Kalkbrenner’s study, published this week online at the journal Epidemiology, showed that pollution’s impact on autism rates in North Carolina is similar to results of pollution-autism studies in California – despite weather and climate differences between the two states.
In addition, the work of Kalkbrenner and her colleagues, building on previous studies, showed that women in the third trimester of pregnancy were more susceptible to the damaging effects of air pollution on their unborn child.
“It adds another piece supporting the hypothesis that environmental chemicals are part of the autism puzzle,” says Kalkbrenner, an assistant professor in UWM’s Joseph J. Zilber School of Public Health. Autism, a spectrum of disorders affecting interpersonal relations and work achievement, now affects some 1 in 68 children in the U.S.
Her research team focused on exposure to coarse and fine particulate matter, known as PM10, which arises in part from traffic-related air pollution. The study evaluated records in the two states, covering pre-conception through the first birthday for 87,000 children in North Carolina and 77,500 in California born in the mid-to-late 1990s. Key regions in each state were selected based on researchers’ ability to simultaneously measure the level of particulate matter present, and know which children had autism in these regions.
Researchers used a new, more exact tool to measure the levels of particulate matter in smaller slices of time, based on pollution at the family’s address during pregnancy. With this method, they were able to compare exposures during specific weeks of pregnancy. The approximately one thousand children who later developed some form of autism spectrum disorders were then compared to all other children.
Kalkbrenner says it was important to look at eastern states because of the differences in climate, seasonal weather patterns and the chemical make-up of the particulate matter that might impact brain development. “Evidence for a link between a chemical exposure and a health impact like autism is stronger when it can be shown in more than one region.” The team found that the concentration of particulate matter was highest among children born in summer months in North Carolina and those born in fall and winter months in California.
Reasons for increased susceptibility in the third trimester of pregnancy are not known at this time. However, Kalkbrenner says this finding is consistent with theories that show links between autism and altered brain network development, specifically synaptic connections that are developing during the final months of pregnancy.
“We’ve now had three solid studies saying the same thing. The evidence is pretty compelling that something is going on with air pollution and autism,” says Kalkbrenner, who adds that further study is needed to determine the neurodevelopmental impacts of specific chemical pollutants during precise developmental windows.
Choosing between two good things can be tough. When animals must decide between feeding and mating, it can get even trickier. In a discovery that might ring true even for some humans, researchers have shown that male brains – at least in nematodes – will suppress the ability to locate food in order to instead focus on finding a mate.
(Image caption: C. elegans male (top) and hermaphrodite (bottom))
The results, which appear today in the journal Current Biology, may point to how subtle changes in the brain’s circuitry dictate differences in behavior between males and females.
“While we know that human behavior is influenced by numerous factors, including cultural and social norms, these findings point to basic biological mechanisms that may not only help explain some differences in behavior between males and females, but why different sexes may be more susceptible to certain neurological disorders,” said Douglas Portman, Ph.D., an associate professor in the Department of Biomedical Genetics and Center for Neural Development and Disease at the University of Rochester and lead author of the study.
The findings were made in experiments involving C. elegans, a microscopic roundworm that has long been used by researchers to understand fundamental mechanisms in biology. Many of the discoveries made using C. elegans apply throughout the animal kingdom and this research has led to a broader understanding of human biology. In fact, three Nobel Prizes in medicine and chemistry have been awarded for discoveries involving C. elegans.
C. elegans is particularly useful in the study of the nervous system and scientists understand in great detail the development, function, and multiple connections of its entire neural network.
The study published today focuses on the activity of a single pair of neurons found in C. elegans – called AWA – that control smell. Smell, along with taste and touch, are critical sensory factors that dictate how C. elegans understands and navigates its environment, including finding food, avoiding danger, and locating a mate.
There are two sexes of C. elegans, males and hermaphrodites. Though the hermaphrodites are able to self-fertilize, they are also mating partners for males, and are considered to be modified females.
It has been previously observed that males and hermaphrodites act differently when exposed to food. If placed at a food source, the hermaphrodites tend to stay there. Males, however, will leave food source and “wander” – scientist believe they do this because they are in search of a mate.
The Rochester researchers discovered that the sensory mechanisms – called chemoreceptors – of the AWA neurons were regulated by the sexual identity of these cells, which, in turn, controls the expression of a receptor called ODR-10. These receptors bind to a chemical scent that is given off by food and other substances.
In hermaphrodites, more of the ODR-10 receptors are produced, making the worms more sensitive – and thereby attracted – to the presence of food. In males, fewer of these receptors are active, essentially suppressing their ability – and perhaps desire – to find food. However, when males were deprived of food, they produced dramatically higher levels of this receptor, allowing them to temporarily focus on finding food.
To confirm the role of these genetic differences between the sexes on behavior, the researchers designed a series of experiments in which they observed the activity of C. elegans when placed in a petri-dish and confronted with the option to either feed or go in search of a mate. The hermaphrodites were place in the center of the dish at a food source and, as expected, they stayed put.
The males were placed in their own individual food sources at the periphery of the dish. As a further obstacle between the males and their potential mates, an additional ring of food surrounded the hermaphrodites in the center of the dish. The males in the experiment consisted of two categories, one group with a normal genetic profile and another group that had been engineered by the researchers to overexpress the ODR-10 receptor, essentially making them more sensitive to the smell of food.
The researchers found that the normal worms left their food source and eventually made their way to the center of the dish where they mated with the hermaphrodites. The genetically engineered males were less successful at finding a mate, presumably because they were more interested in feeding. By examining the genetic profile of the resulting offspring, the scientists observed that the normal males out-produced the genetically engineered males by 10 to one.
In separate experiments, the researchers were also able to modify the behavior of the hermaphrodites by suppressing the ODR-10 receptors, causing them to act like males and abandon their food source.
“These findings show that by tuning the properties of a single cell, we can change behavior,” said Portman. “This adds to a growing body of evidence that sex-specific regulation of gene expression may play an important role in neural plasticity and, consequently, influence differences in behaviors – and in disease susceptibility – between the sexes.”
An important scientific breakthrough by a team of IRCM researchers led by Michel Cayouette, PhD, is being published today by The Journal of Neuroscience. The Montréal scientists discovered that a protein found in the retina plays an essential role in the function and survival of light-sensing cells that are required for vision. These findings could have a significant impact on our understanding of retinal degenerative diseases that cause blindness.
The researchers studied a process called compartmentalization, which establishes and maintains different compartments within a cell, each containing a specific set of proteins. This process is crucial for neurons (nerve cells) to function properly.
“Compartments within a cell are much like different parts of a car,” explains Vasanth Ramamurthy, PhD, first author of the study. “In the same way that gas must be in the fuel tank in order to power the car’s engine, proteins need to be in a specific compartment to properly exercise their functions.”
A good example of compartmentalization is observed in a specialized type of light-sensing neurons found in the retina, the photoreceptors, which are made up of different compartments containing specific proteins essential for vision.
“We wanted to understand how compartmentalization is achieved within photoreceptor cells,” says Dr. Cayouette, Director of the Cellular Neurobiology research unit at the IRCM. “Our work identified a new mechanism that explains this process. More specifically, we found that a protein called Numb functions like a traffic controller to direct proteins to the appropriate compartments.”
“We demonstrated that in the absence of Numb, photoreceptors are unable to send a molecule essential for vision to the correct compartment, which causes the cells to progressively degenerate and ultimately die,” adds Dr. Ramamurthy, who carried out the project in Dr. Cayouette’s laboratory in collaboration with Christine Jolicoeur, research assistant. “This is important because the death of photoreceptor cells is known to cause retinal degenerative diseases in humans that lead to blindness. Our work therefore provides a new piece of the puzzle to help us better understand how and why the cells die.”
“We believe our results could eventually have a substantial impact on the development of treatments for retinal degenerative diseases, like retinitis pigmentosa and Leber’s congenital amaurosis, by providing novel drug targets to prevent photoreceptor degeneration,” concludes Dr. Cayouette.
According to the Foundation Fighting Blindness Canada, millions of people in North America live with varying degrees of irreversible vision loss because they have an untreatable, degenerative eye disorder that affects the retina. Research aiming to better understand what causes vision loss could lead to preserving and restoring sight.
Mutations in a gene called LRRK2 carry a well-established risk for Parkinson’s disease, however the basis for this link is unclear.
(Image caption: A microscope image of a cultured cell)
The team, led by Parkinson’s UK funded researchers Dr Kurt De Vos from the Department of Neuroscience and Dr Alex Whitworth from the Department of Biomedical Sciences, found that certain drugs could fully restore movement problems observed in fruit flies carrying the LRRK2 Roc-COR Parkinson’s mutation.
These drugs, deacetylase inhibitors, target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells. The study is published in Nature Communications.
Dr De Vos, a Lecturer in Translational Neuroscience at the world-leading Sheffield Institute for Translational Neuroscience (SITraN), said: “Our study provides compelling evidence that there is a direct link between defective transport within nerve cells and movement problems caused by the LRRK2 Parkinson’s mutation in flies.”
Co-investigator Dr Alex Whitworth explained: “We could also show that these neuronal transport defects caused by the LRRK2 mutation are reversible.
“By targeting the transport system with drugs, we could not only prevent movement problems, but also fully restore movement abilities in fruit flies who already showed impaired movement marked by a significant decrease in both climbing and flight ability.”
The LRRK2 gene produces a protein that affects many processes in the cell. It is known to bind to the microtubules, the cells’ transport tracks. A defect in this transport system has been suggested to contribute to Parkinson’s disease. The researchers have investigated this link and have now found the evidence that certain LRRK2 mutations affect transport in nerve cells which leads to movement problems observed in the fruit fly (Drosophila).
The team then used several approaches to show that preventing the association of the mutant LRRK2 protein with the microtubule transport system rescues the transport defects in nerve cells, as well as the movement deficits in fruit flies.
Dr De Vos added: “We successfully used drugs called deacetylase inhibitors to increase the acetylated form of α-tubulin within microtubules which does not associate with the mutant LRRK2 protein. We found that increasing microtubule acetylation had a direct impact on cellular axonal transport.
“These are very promising results which point to a potential Parkinson’s therapy. However, further studies are needed to confirm that this rescue effect also applies in humans.“
Dr Beckie Port, Research Communications Officer at Parkinson’s UK, which helped to fund the study, said: “This research gives hope that, for people with a particular mutation in their genes, it may one day be possible to intervene and stop the progression of Parkinson’s.
“The study has only been carried out in fruit flies, so much more research is needed before we know if these findings could lead to new treatment approaches for people with Parkinson’s.”