Posts tagged genetics
Posts tagged genetics
Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein that is linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson’s, Alzheimer’s and autism.
"This receptor family is an exciting new target for future medicines for treatment of brain disorders," said P. Jeffrey Conn, PhD, Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery, who was a senior author of the study with Raymond Stevens, PhD, a professor in the Department of Integrative Structural and Computational Biology at TSRI. "This new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts."
The research—which focuses on the mGlu1 receptor—was reported in the March 6, 2014 issue of the journal Science.
A Family of Drug Targets
The mGlu1 receptor, which helps regulate the neurotransmitter glutamate, belongs to a superfamily of molecules known as G protein-coupled receptors (GPCRs).
GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters and light. After binding these molecules, GPCRs trigger a specific response inside the cell. More than one-third of therapeutic drugs target GPCRs—including allergy and heart medications, drugs that target the central nervous system and anti-depressants.
The Stevens lab’s work has revolved around determining the structure and function of GPCRs. GPCRs are not well understood and many fundamental breakthroughs are now occurring due to the understanding of GPCRs as complex machines, carefully regulated by cholesterol and sodium.
When the Stevens group decided to pursue the structure of mGlu1 and other key members of the mGlu family, it was natural the scientists reached out to the researchers at Vanderbilt. “They are the best in the world at understanding mGlu receptors,” said Stevens. “By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling.”
Colleen Niswender, PhD, director of Molecular Pharmacology and research associate professor of Pharmacology at the Vanderbilt Center for Neuroscience Drug Discovery, also thought the collaboration made sense. “This work leveraged the unique strengths of the Vanderbilt and Scripps teams in applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships to validate the receptor structure,” she said.
The Challenge of the Unknown
mGlu1 was a particularly challenging research topic.
In general, GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge. And the mGlu1 receptor is particularly tricky as, in addition to the domain spanning the membrane, it has a large domain extending into the extracellular space. Moreover, two copies of this multidomain receptor associating in a dimer are needed to transmit glutamate’s signal across the membrane.
The task was made more difficult because there was no template for mGlu1 from closely related GPCR proteins to guide the researchers.
“mGlu1 belongs to class C GPCRs, of which no structure has been solved before,” said TSRI graduate student Chong Wang, a first author of the new study with TSRI graduate student Huixian Wu. “This made the project much harder. We could not use other GPCRs as a template to design constructs for expression and stabilization or to help interpret diffraction data. The structure was so different that old school methods in novel protein structure determination had to be used.”
The team decided to try to determine the structure of mGlu1 bound to novel “allosteric modulators” of mGlu1 contributed by the Vanderbilt group. Allosteric modulators bind to a site far away from the binding site of the natural activator (in this case, presumably the glutamate molecule), but change the shape of the molecule enough to affect receptor function. In the case of allosteric drug candidates, the hope is that the compounds affect the receptor function in a desirable, therapeutic way.
"Allosteric modulators are promising drug candidates as they can ‘fine-tune’ GPCR function,” said Karen Gregory, a former postdoctoral fellow at Vanderbilt University, now at Monash Institute of Pharmaceutical Sciences. “However, without a good idea of how drug-like compounds interact with the receptor to adjust the strength of the signal, discovery efforts are challenging."
The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu1 in complex with one of the drug candidates, as well as a deeper understanding of the receptor’s function and pharmacology.
The findings show that mGlu1 possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance.
“Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for the binding of allosteric modulators,” said Vsevolod “Seva” Katritch, assistant professor of molecular biology at TSRI and a co-author of the paper. “This is very important for understanding action of the allosteric modulator drugs and may partially explain difficulties in screening for such drugs.
“The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors,” he continued, “some of which are equally important in drug discovery.”
A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.
(Image caption: A key brain signaling protein, seen here in green, that is normally lost in Fragile X syndrome neurons is restored by an experimental drug. Image: Dilek Colak)
Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren’t sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.
Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene’s DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.
"Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient’s lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene’s DNA, shutting down the gene — which was not known before.
"This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," Dr. Jaffrey says. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting."
The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. At that point, the messenger RNA produced by the fragile X syndrome gene makes what the researchers call an RNA-DNA duplex — a particular arrangement of molecules in which the messenger RNA is stuck onto its DNA complement. (DNA produces two complementary strands of the genetic code responsible for human development and function. The four nucleic acids in the genomic code — A, C, G, T — have specific complements. In the case of fragile X syndrome, the repeat sequence in question is CGG. Therefore, RNA binds to its GCC complement on one strand of DNA.)
The RNA-DNA duplex then shuts down production of the fragile X syndrome gene, causing the loss of a protein needed for communication between brain cells. The gene then remains inactive for life. A normal fragile X gene — one with fewer than 200 CGG repeats — stays active in a person without the disorder, and produces the necessary protein. However, the mutant fragile X gene contains more than 200 CGG repeats, resulting in fragile X syndrome. Fragile X occurs in about 1 in 4,000 males and 1 in 8,000 females.
"Because the fragile X syndrome mutation is a repeat sequence, it is very easy for just a small portion of this sequence in the messenger RNA to find a matching repeat sequence on the DNA," Dr. Jaffrey says. "This is a unique feature of repeat sequences. When there are 200 or more repeats, the RNA-DNA interaction locks into place."
Hope for treatment — and other disorders
Dr. Jaffrey and his team, which includes researchers from The Scripps Research Institute in Florida and Albert Einstein College of Medicine in the Bronx, sought to find out why the disease is switched on when the CGG repeat is present in 200 to as many as 1,000 copies.
"Utilizing traditional ways to solve this puzzle has been impossible," he says. "Human fragile X syndrome genes introduced into mice and cells in the laboratory never turn off, no matter how many CGG repeats the genes have."
So the scientists turned to human embryonic stem cells. Co-authors Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, and Dr. Nikica Zaninovic, assistant professor of reproductive medicine, generated stem cell lines from donated embryos that tested positive for fragile X syndrome. “These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development,” says Dr. Dilek Colak, a postdoctoral scientist in Dr. Jaffrey’s laboratory and the first author of the study.
The stem cells were coaxed to become brain neurons, and at about 50 days, they differentiated in the same way that an embryo’s brain is developing at 11-plus weeks when the fragile X syndrome gene is switched off.
The researchers then used a drug developed by co-author Dr. Matthew Disney of the Scripps Research Institute that binds to CGG in the fragile X gene’s RNA before and after the 50-day switch. Strikingly, the gene never stopped producing its beneficial protein.
That suggests a potential prevention or treatment strategy for fragile X syndrome, Dr. Jaffrey says. “If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients,” he says.
The researchers are now looking for similar RNA-DNA duplexes in other trinucleotide repeat diseases, including Huntington’s disease (a degenerative brain disease), myotonic dystrophy 1 and 2 (a multisystem progressive disease), Friedrich’s ataxia (a progressive nervous system disorder), Jacobsen syndrome (an intellectual disorder), and familial amyotrophic lateral sclerosis (a motor neuron disease), among others.
"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Dr. Jaffrey says. "Our hope is that we can find drugs that interfere with this new type of disease process."
UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.
Although the research indicates it may someday be possible to regenerate neurons from the body’s own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer’s disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.
Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.
Scientists in UT Southwestern’s Department of Molecular Biology first successfully turned astrocytes – the most common non-neuronal brain cells – into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.
“Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons,” said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies.
“Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration,” Dr. Zhang explained. “Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming.”
The scientists’ two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.
In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.
The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.
In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added.
Because tumor growth is a concern when cells are reprogrammed to an earlier stage of development, the researchers followed the mice in the Nature Cell Biology study for nearly a year to look for signs of tumor formation and reported finding none.
A team of international scientists, including a researcher from Simon Fraser University, has isolated a gene thought to play a causal role in the development of Alzheimer’s disease. The Proceedings of the National Academy of Sciences recently published the team’s study.
The newly identified gene affects accumulation of amyloid-beta, a protein believed to be one of the main causes of the damage that underpins this brain disease in humans.
The gene encodes a protein that is important for intracellular transportation. Each brain cell relies on an internal highway system that transports molecular signals needed for the development, communication, and survival of the cell.
This system’s impairment can disrupt amyloid-beta processing, causing its eventual accumulation. This contributes to the development of amyloid plaques, which are a key hallmark of Alzheimer’s disease.
Teasing out contributing disease factors, whether genetic or environmental, has long posed a challenge for Alzheimer’s researchers.
“Alzheimer’s is a multifactorial disease where a build-up of subtle problems develop in the nervous system over a span of decades,” says Michael Silverman, an SFU biology associate professor. He worked on the study with a team of Japanese scientists led by Dr. Takashi Morihara at Osaka University.
Identifying these subtle, yet perhaps critical genetic contributions is challenging. “Alzheimer’s, like many human disorders, has a genetic component, yet many environmental and lifestyle factors contribute to the disease as well,” says Silverman. “In a sense, it is like looking for a needle in a complex genetic haystack.”
Only a small fraction of cases have a strong hereditary component, for example early-onset Alzheimer’s.
This breakthrough in Alzheimer’s research could open new avenues for the design of therapeutics and pave the way for early detection by helping healthcare professionals identify those who are predisposed to the disease.
“One possibility is that a genetic test for a particular variant of this newly discovered gene, along with other variants of genes that contribute to Alzheimer’s, will help to give a person their overall risk for the disease.
“Lifestyle changes, such as improved diet, exercise, and an increase in cognitive stimulation may then help to slow the progression of Alzheimer’s,” says Silverman.
Geneticists from Trinity College Dublin interested in ‘reverse engineering’ the nervous system have made an important discovery with wider implications for repairing missing or broken links. They found that the same molecular switches that induce originally non-descript cells to specialise into the billions of unique nerve cell types are also responsible for making these nerve cells respond differently to the environment.
The geneticists are beginning to understand how these molecular switches, called ‘transcription factors’, turn on specific cellular labels to form complex bundles of nerves. These bundles function to ensure we respond and react appropriately to the incredible amount of information our brains encounter. Understanding how to precisely program nerve cells could help to target missing or broken links following serious injury or the onset of degenerative diseases such as Alzheimer’s or Parkinson’s.
Commenting on the importance and wider implications of this discovery, Assistant Professor in Genetics at Trinity, Juan Pablo Labrador said: “We know very little of how individual nerve cells are programmed to assemble into specific nerves in living organisms to make specific circuits, so our work is like reverse engineering the nervous system.”
“To restore damaged or missing connections in the nervous system – for example, after spinal cord injuries or degenerative diseases such as Alzheimer’s or Parkinson’s – we need to know how nerve cells are programmed to make those connections in the first place. For that we require a complex ‘builder’s manual’ that tells us how to program the neurons to make the connections. What we are doing in my lab is trying to write this manual.”
The nervous system can be thought of as an incredibly complex network of wires, which are all arranged into different, related bundles to coordinate complex tasks. The wires are the cellular extensions from the individual nerve cells that assemble into bundles to form specific nerves. The geneticists have begun to understand how varied combinations of transcription factors work to generate different nerve cells and direct their wiring to form specific nerves.
By studying the behaviour of individual nerve cells that make connections with muscles, the geneticists discovered specific ‘footprints’ of labels that induced these nerve cells to assemble into specific bundles that link to their target muscles. Individual transcription factors are only able to turn on specific labels to some extent. It is only the action of all of them together that programmes the nerve cells to turn on all the labels required.
The research was just published in the high-profile journal Neuron. The team led by Assistant Professor Juan Pablo Labrador, found that the actions of the transcription factor influencing nerve cell differentiation in flies (‘Eve’) controls nerve cell surface labels.
The team also showed that if these labels, targeted by Eve, are expressed erroneously, the nerve cells will not form the correct nerves. Additionally, the team discovered that different combinations of transcription factors including Eve work as codes for different groups of labels that guide individual nerve development.
The nature of the machinery responsible for the entry of proteins into cell membranes has been unravelled by scientists, who hope the breakthrough could ultimately be exploited for the design of new anti-bacterial drugs.
Groups of researchers from the University of Bristol and the European Molecular Biology Laboratory (EMBL) used new genetic engineering technologies to reconstruct and isolate the cell’s protein trafficking machinery. Its analysis has shed new light on a process which had previously been a mystery for molecular biologists.
The findings, published this week in the Proceedings of the National Academy of Sciences (PNAS), could also have applications for synthetic biology - an emerging field of science and technology, for the development of novel membrane proteins with useful activities.
Proteins are the building blocks of all life and are essential for the growth of cells and tissue repair. The proteins in the membrane typically help the cell interact with its environment and conserve energy.
Researchers were able to identify the ‘holo-translocon’ as the machinery which inserts proteins into the membrane. It is a large membrane protein complex and is uniquely capable of both protein-secretion and membrane-insertion.
Professor Ian Collinson, from the School of Biochemistry at Bristol University, said: “These findings are important as they address outstanding questions in one of the central pillars of biology, a process essential in every cell in every organism. Having unravelled how this vital holo-translocon works, we’re now in a position to look at its components to see if they can help in the design or screening for new anti-bacterial drugs.”
Boys are at greater risk for delayed language development than girls, according to a new study using data from the Norwegian Mother and Child Cohort Study. The researchers also found that reading and writing difficulties in the family gave an increased risk.
“We show for the first time that reading and writing difficulties in the family can be the main reason why a child has a speech delay that first begins between three to five years of age,” says Eivind Ystrøm, senior researcher at the Norwegian Institute of Public Health.
Ystrøm was supervisor of Imac Maria Zambrana, a former PhD student at the Norwegian Institute of Public Health who conducted the research in this study as part of her doctoral research.
The researchers used data from questionnaires completed by the mothers who are participating in the Norwegian Mother and Child Cohort Study (MoBa). The study included more than 10,000 children from week 17 of pregnancy up to five years of age.
“MoBa is a large study with a normal cross-section of the population. It gives us a unique opportunity to examine changes over time, the scope and any risk factors for delayed language development,” says Ystrøm.
The researchers classified the language difficulties at three and five years of age in three groups: persistent delayed language development (present at both times), transient delayed language development (only present at three years) and delayed language development first identified at five years old.
Boys are in the majority for the groups with persistent and transient language difficulties. Ystrøm explains that boys are biologically at greater risk for developmental disorders in utero than girls. British scientists have measured the male sex hormone (testosterone) in amniotic fluid and they found that the levels were related to the development of both autism and language disorders. Ystrøm points out that boys are generally a little later in language development than girls, but that most catch up during the first year. Therefore, many boys could be at risk of persistent language impairment and increasingly have transient language difficulties that disappear before school age.
The researchers found that gender was irrelevant for the third group who have language difficulties that begin sometime between three and five years of age.
We have good knowledge about normal language development in children. Many genes are important for language development and research suggests that different genes are involved in different types of language difficulty.
“Reading and writing difficulties in the family are the predominant risk factors for late-onset language difficulties. We see no language problems when the child is between 18 months and three years old. They are latent” says Ystrøm.
The researchers believe that both specific genes and factors in the child’s external environment can lead to delays in language development at three to five years of age.
What can we do?
Ystrøm believes that children with delayed language development must be identified as early as possible. Parents, health care workers and child care staff should be aware of the language development of children and encourage an enabling language environment, in some cases with specially adapted measures. In particular, they must be aware of children who have sustained disabilities, or who have had normal language development up to three years and then unexpectedly began to have difficulties.
“Professionals and caregivers must be vigilant. It is difficult to detect language difficulties when language becomes more complex in older children. They must be trained so that they are confident in how to spot language difficulties and how to encourage a child’s language. We need more research into the needs of children with different trajectories”, says Ystrøm.
Parents who are concerned about their child’s language development should consult their doctor. They should also raise the issue at the regular check-ups at the health clinic when the child is between two and four years old.
“The checks must take place at the appropriate time. It is important that they are not delayed or not implemented at all,” says Ystrøm.
A few years ago, a survey by the Health and Welfare Department in Oslo showed that few of the health centres in Oslo met the required 14 consultations for each child from birth to school stipulated by the Norwegian Directorate of Health.
In addition to researchers at the Norwegian Institute of Public Health, researchers at the University of Oslo and the University of Melbourne in Australia participated in this study. The work is funded by the Extra Foundation for Health and Rehabilitation.
“We hope to continue this research and specifically look at the relationship between gender and language. We need more research into the needs of children with various types of language delay”, says Eivind Ystrøm.
Zambrana, IM, Pons, F., Eadie, P. and Ystrom, E. (2013). Trajectories of language delay from age 3 to 5: persistence, recovery and late onset. International Journal of Language & Communication
For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment.
The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.
An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.
Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”
She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.”
The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.
To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.
The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.
Scientists have discovered a link between a largely unstudied gene and schizophrenia.
They also found a link between the same gene and bipolar disorder, depression and autism.
The University of Aberdeen-led research - published in the Journal of Cell Science - set out to look for genes that might be important for schizophrenia.
During analysis of five major patient cohorts, scientists picked out the poorly-understood gene ULK4 which has previously been associated with hypertension but never before with mental health disorders.
They discovered that a mutation of the gene ULK4 was found far more frequently in patients with schizophrenia.
Researchers also found mutation of ULK4 in some people with bipolar disorder, depression and autism.
First author Dr Bing Lang, Research Fellow at the University of Aberdeen, said: “Schizophrenia is a severe psychiatric disorder affecting about 1% of the population. Genetics are estimated to be between 60 and 80% responsible for the condition, but very few specific susceptibility genes for schizophrenia have been firmly confirmed in humans.
“However our results suggest that mutation of the gene UKL4 can be a rare genetic risk factor for schizophrenia as well as other psychiatric disorders.”
The researchers found evidence that ULK4 regulates many important signalling pathways within nerve cells involved in schizophrenia and stress.
They also discovered that mutation of the gene reduced communication between brain cells.
Professor Colin McCaig, one of the researchers and Head of the University’s School of Medical Sciences, added: “This is an important discovery of a gene involved in major mental health disorders which affects basic nerve cell growth and nerve to nerve communication. We expect it will form another important piece of the jigsaw that will produce a fuller understanding of what goes wrong in the brain in conditions such as schizophrenia.”
Dr Lang added: “We are very excited by our findings. We still need to do much more work to understand the mechanisms underlying the role of UKL4 in schizophrenia in the hope that this may lead to the discovery of new drug targets for a condition that deprives some sufferers of the ability to lead normal, independent lives.”
Image caption: MMP-9 controls onset of paralysis in ALS mice. Sections of muscle stained for nerve (green) and muscle (red); nerve-muscle contacts appear yellow. In the SOD1 mouse, muscles that move the eye (left) retain nerve contacts and are active. Fast leg muscles (center) in the same animal lose nerve contacts (red stain only) and become paralyzed. Fast muscles from which MMP-9 has been genetically removed (right) retain their nerve contacts, and therefore muscle function, for nearly 3 months longer. This suggests that inhibiting MMP-9 in human patients with ALS should be beneficial. Credit: The Henderson Lab/Columbia University Medical Center.
Columbia University Medical Center (CUMC) researchers have identified a gene, called matrix metalloproteinase-9 (MMP-9), that appears to play a major role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The findings, made in mice, explain why most but not all motor neurons are affected by the disease and identify a potential therapeutic target for this still-incurable neurodegenerative disease. The study was published today in the online edition of the journal Neuron.
“One of the most striking aspects of ALS is that some motor neurons—specifically, those that control eye movement and eliminative and sexual functions—remain relatively unimpaired in the disease,” said study leader Christopher E. Henderson, PhD, the Gurewitsch and Vidda Foundation Professor of Rehabilitation and Regenerative Medicine, professor of pathology & cell biology and neuroscience (in neurology), and co-director of Columbia’s Motor Neuron Center. “We thought that if we could find out why these neurons have a natural resistance to ALS, we might be able to exploit this property and develop new therapeutic options.”
To understand why only some motor neurons are vulnerable to ALS, the researchers used DNA microarray profiling to compare the activity of tens of thousands of genes in neurons that resist ALS (oculomotor neurons/eye movement and Onuf’s nuclei/continence) with neurons affected by ALS (lumbar 5 spinal neurons/leg movement). The neurons were taken from normal mice.
“We found a number of candidate ‘susceptibility’ genes—genes that were expressed only in vulnerable motor neurons. One of those genes, MMP-9, was strongly expressed into adulthood. That was significant, as ALS is an adult-onset disease,” said co-lead author Krista J. Spiller, a former graduate student in Dr. Henderson’s laboratory who is now a postdoctoral fellow at the University of Pennsylvania. The other co-lead author is Artem Kaplan, a former MD-PhD student in the lab who is now a neurology resident at NewYork-Presbyterian Hospital/Columbia University Medical Center.
In a follow-up experiment, the researchers confirmed that the product of MMP-9, MMP-9 protein, is present in ALS-vulnerable motor neurons, but not in ALS-resistant ones. Further, the researchers found that MMP-9 can be detected not just in lumbar 5 neurons, but also in other types of motor neurons affected by ALS. “It was a perfect correlation.” said Dr. Henderson. “In other words, having MMP-9 is an absolute predictor that a motor neuron will die if the disease strikes, at least in mice.”
Taking a closer look at the groups of vulnerable motor neurons, the researchers found differences in MMP-9 expression at the single-cell level. Fast-fatigable neurons (which are involved in movements like jumping and sprinting and are the first to die in ALS) were found to have the most MMP-9 protein, whereas slow neurons (which control posture and are only partially affected in ALS) had none. “So, MMP-9 is not only labeling the most vulnerable groups of motor neurons, it is labeling the most vulnerable subtypes within those groups, as well,” said Dr. Spiller.
In another experiment, the researchers tested whether MMP-9 has afunctional role in ALS by crossing MMP-9 knockout mice with SOD1 mutant mice (a standard mouse model of ALS). Progeny from this cross with no MMP-9 exhibited an 80-day delay in loss of fast-fatigable motor neuron function and a 25 percent longer lifespan, compared with littermates with two copies of the MMP-9 gene. “This effect on nerve-muscle synapses is the largest ever seen in a mouse model of ALS,” said Dr. Spiller.
The same effect on motor neuron function was seen when MMP-9 was inactivated in SOD1 mutant mice using chemical injections or virally mediated gene therapy.
“Even after treatment, these mice didn’t have a normal lifespan, so inactivating MMP-9 is not a cure,” said Dr. Henderson. “But it’s remarkable that lowering levels of a single gene could have such a strong effect on the disease. That’s encouraging for therapeutic purposes.”
The researchers are still investigating how MMP-9 affects motor neuron function. Their findings suggest that the protein plays a role in increasing stress on the endoplasmic reticulum, an organelle involved in transporting and processing materials within cells. “Our goal is to learn more about MMP-9 and related pathways and to identify a new set of therapeutic targets,” said Dr. Henderson.