Posts tagged genetics
Articles and news from the latest research reports.
New gene for bipolar disorder discovered
Team of researchers searched for the foundations of manic-depressive disorder in about 24,000 people
First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from the University of Bonn Hospital, the Central Institute of Mental Health of Mannheim and the University of Basel Hospital, an international collaboration of researchers discovered two new gene regions which are connected with the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal “Nature Communications”.
Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts. The causes of the disease are not yet fully understood, however in addition to psychosocial triggers, genetic factors play a large role. “There is no one gene that has a significant effect on the development of bipolar disorder,” says Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics of the University of Bonn Hospital. “Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”
Scale of the investigation is unparalleled worldwide
In recent years, scientists at the Institute of Human Genetics were already involved in decoding several genes associated with bipolar disorder. The researchers working with Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health of Mannheim, Prof. Dr. Markus M. Nöthen from the University of Bonn Hospital and Prof. Dr. Sven Cichon from the University of Basel Hospital are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2266 patients with manic-depressive disorder and 5028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9747 patients were compared with data from 14,278 healthy persons. “The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date,” says Prof. Rietschel from the Central Institute of Mental Health of Mannheim.
The search for genes involved in manic-depressive disorder is like looking for a needle in a haystack. “The contributions of individual genes are so minor that they normally cannot be identified in the ‘background noise’ of genetic differences,” explains Prof. Cichon from the University of Basel Hospital. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes.
Two new gene regions discovered and three known gene regions confirmed
Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene “ADCY2” on chromosome five and the so-called “MIR2113-POU3F2” region on chromosome six. The risk regions “ANK3”, “ODZ4” and “TRANK1” have already been described in prior studies. “These gene regions were, however, statistically better confirmed in our current investigation - the connection with bipolar disorder has now become even clearer,” says Prof. Nöthen.
The researchers are particularly interested in the newly discovered gene region “ADCY2”. It codes an enzyme which is involved in the conduction of signals into nerve cells. “This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains the human geneticist of the University of Bonn Hospital. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. “Only when we know the biological foundations of this disease can be also identify starting points for new therapies,” says Prof. Nöthen.
Critical role of one gene to our brain development
New research from the University of Adelaide has confirmed that a gene linked to intellectual disability is critical to the earliest stages of the development of human brains.
Known as USP9X, the gene has been investigated by Adelaide researchers for more than a decade, but in recent years scientists have begun to understand its particular importance to brain development.
In a new paper published online in the American Journal of Human Genetics, an international research team led by the University of Adelaide’s Robinson Research Institute explains how mutations in USP9X are associated with intellectual disability. These mutations, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning.
Speaking during Brain Awareness Week, senior co-author Dr Lachlan Jolly from the University of Adelaide’s Neurogenetics Research Program says the USP9X gene has shed new light on the mysteries of brain development and disability.
Dr Jolly says the base framework for the brain’s complex network of cells begins to form at the embryo stage.
"Not surprisingly, disorders that cause changes to this network of cells, such as intellectual disabilities, epilepsy and autism, are hard to understand, and treat," Dr Jolly says.
"By looking at patients with severe learning and memory problems, we discovered a gene - called USP9X - that is involved in creating this base network of nerve cells. USP9X controls both the initial generation of the nerve cells from stem cells, and also their ability to connect with one another and form the proper networks,” he says.
"This work is critical to understanding how the brain develops, and how it is altered in individuals with brain disorders.
"We hope that by learning more about genes such as USP9X, we will create new opportunities to understand brain disorders at a much deeper level than currently known, which could lead to future treatment opportunities.”
How a small worm may help the fight against Alzheimer’s
Scientists at the Max Planck Institute for Biology of Ageing in Cologne have found that a naturally occurring molecule has the ability to enhance defense mechanisms against neurodegenerative diseases. Feeding this particular metabolite to the small round worm Caenorhabditis elegans, helps clear toxic protein aggregates in the body and extends life span.
During ageing, proteins in the human body tend to aggregate. At a certain point, protein aggregation becomes toxic, overloads the cell, and thus prevents it from maintaining normal function. Damage can occur, particularly in neurons, and may result in neurodegenerative diseases like Alzheimer’s, Parkinson’s or Huntington’s disease. By studying model organisms like Caenorhabditis elegans, scientists have begun to uncover the mechanisms underlying neurodegeneration, and thus define possible targets for both therapy and prevention of those diseases. “Although we cannot measure dementia in worms“, explains Martin Denzel of the Max Planck Institute for Biology of Ageing, “we can observe proteins that we also know from human diseases like Alzheimer’s to be toxic by measuring effects on neuromuscular function. This gives us insight into how Alzheimer actually progresses on the molecular level“.
Now, the scientists Martin Denzel, Nadia Storm, and Max Planck Director Adam Antebi have discovered that a substance called N-acetylglucosamine apparently stimulates the body’s own defense mechanism against such toxicity. This metabolite occurs naturally in the organism. If it is additionally fed to the worm, “we can achieve very dramatic benefits“, says Denzel. “It is a broad-spectrum effect that alleviates protein toxicity in Alzheimer’s, Parkinson’s and Huntington’s disease models in the worm, and it even extends their life span.“
This molecule apparently plays a crucial role in quality control mechanisms that keep the body healthy. It helps the organism to clear toxic levels of protein aggregation, both preventing aggregates from forming and clearing already existing ones. As a result, onset of paralysis is delayed in models of neurodegeneration - How exactly the molecule achieves this effect is yet to be uncovered. “And we still don’t know whether it also works in higher animals and humans“, says Antebi. “But as we also have these metabolites in our cells, this gives good reason to suspect that similar mechanisms might work in humans.”
Restoring Order in the Brain
Alzheimer’s disease is the most widespread degenerative neurological disorder in the world. Over five million Americans live with it, and one in three senior citizens will die with the disease or a similar form of dementia. While memory loss is a common symptom of Alzheimer’s, other behavioral manifestations — depression, loss of inhibition, delusions, agitation, anxiety, and aggression — can be even more challenging for victims and their families to live with.
Now Prof. Daniel Offen and Dr. Adi Shruster of Tel Aviv University’s Sackler School of Medicine have discovered that by reestablishing a population of new cells in the part of the brain associated with behavior, some symptoms of Alzheimer’s disease significantly decreased or were reversed altogether.
The research, published in the journal Behavioural Brain Research, was conducted on mouse models; it provides a promising target for Alzheimer’s symptoms in human beings as well.
"Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you aged or as the result of injury or disease," said Prof. Offen, who also serves as Chief Scientific Officer at BrainStorm, a biotech company at the forefront of innovative stem cell research. "We now know that stem cells can be used to regenerate areas of the brain."
Speeding up recovery
After introducing stem cells in brain tissue in the laboratory and seeing promising results, Prof. Offen leveraged the study to mice with Alzheimer’s disease-like symptoms. The gene (Wnt3a) was introduced in the part of the mouse brain that controls behavior, specifically fear and anxiety, in the hope that it would contribute to the formation of genes that produce new brain cells.
According to Prof. Offen, untreated Alzheimer’s mice would run heedlessly into an unfamiliar and dangerous area of their habitats instead of assessing potential threats, as healthy mice do. Once treated with the gene that increased new neuron population, however, the mice reverted to assessing their new surroundings first, as usual.
"Normal mice will recognize the danger and avoid it. Mice with the disease, just like human patients, lose their sense of space and reality," said Prof. Offen. "We first succeeded in showing that new neuronal cells were produced in the areas injected with the gene. Then we succeeded in showing diminished symptoms as a result of this neuron repopulation."
"The loss of inhibition is a cause of great embarrassment for most patients and relatives of patients with Alzheimer’s," said Prof. Offen. "Often, patients take off their pants in public, having no sense of their surroundings. We saw parallel behavior in animal models with Alzheimer’s."
Next: Memory
After concluding that increased stem cell production in a certain area of the brain had a positive effect on behavioral deficits of Alzheimer’s, Prof. Offen has moved to research into the area of the brain that controls memory. He and his team are currently exploring it in the laboratory and are confident that the results of the new study will be similar.
"Although there are many questions to answer before this research produces practical therapies, we are very optimistic about the results and feel this is a promising direction for Alzheimer’s research," said Prof. Offen.
(Source: aftau.org)
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.”
Surprising Results
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.”
Scientists Uncover Trigger for Most Common Form of Intellectual Disability and Autism
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."
(Source: weill.cornell.edu)
Researchers generate new neurons in brains, spinal cords of living adult mammals
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.
(Image: Shutterstock)
New risk gene illuminates Alzheimer’s disease
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.
(Source: sfu.ca)
Geneticists Show How Molecular Switches Coordinate the Nervous System
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.
(Source: tcd.ie)
Molecular biology mystery unravelled
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.”