New Protein Related to Down Syndrome

Researchers from the University of Michigan, in the United States, reveal a new aspect related to Down’s syndrome. They managed to observe the impact that up-regulation and down-regulation of a gene related to the syndrome has on the nervous system of the patients. Their discovery could lead to progress in future therapeutic approaches. The neurons of a healthy person begin to develop and expand their protrusions immediately after birth. During this period, each neuron produces high amounts of a protein, known as Dscam (Down syndrome cell-adhesion molecule), which is regulated by the gene. After the growth period of the neurons, the level of protein drops dramatically in healthy patients. However, in patients suffering from Down’s syndrome, with symptoms such as epilepsy, the protein maintains its high levels. The researchers weren’t yet able to discover the effect that the high level of protein has on the development of neurons.

Down Syndrome

Professor Bing Ye, the lead author of the study, discovered that the neuron growth of the Drosophila fly is in direct connection to the amount of Dscam protein present in the cell. Higher levels of Dscam meant that the protrusions of the neuron extended further before forming connections with the other nervous cells, when compared to the protrusions of neurons with lower levels of Dscam protein. Professor Ye and his team also report the discovery of two separate molecular pathways that converge and regulate the levels of Dscam. The first pathway, consisting of the DLK (dual leucine zipper kinase), is responsible for the up-regulation of Dscam proteins. The second pathway, consisting of a FMRP (fragile X mental retardation protein), down-regulates the synthesis of Dscam proteins. Professor Ye explains that these genes are common for humans and Drosophila flies, and so, these pathways could also provide a new therapeutic target against Down’s syndrome.

Precedent studies have already discovered that there are multiple genes involved in the onset and evolution of Down’s syndrome. However, the mechanisms through which the genetic defects produce the disease are still not completely understood. Professor Ye affirms that their new discovery is important because of its role in the development of nervous cells. The researchers are already planning their future studies. Their first attempt will be to see if high levels of Dscam proteins in the nervous cells of laboratory mice has an effect on their behavior and nervous system. Recent estimates show that Down’s syndrome affects 1 in 830 newborns around the world.

Neuronal Regeneration Based on Nervous Cell Design

A research team from the University of Michigan, in the United States, reveals that both halves of our nervous cells are controlled by a single gene. Their discovery, recently published in the online journal PLOS Biology, suggests that in order to be able to develop novel regeneration therapies for nervous cells, this design must be taken into consideration. The research team from the Life Sciences Institute at U-M, led by assistant professor Bing Ye, discovered that when they tried to manipulate the genes of the Drosophila fly to increase the growth of only one part of the neuron, the other part had its growth simultaneously stunted.

According to professor Ye, their observation plays an important role for scientists that are trying to create new therapies for spinal cord injuries, neurodegenerative disorders and other diseases of the nervous system. Professor Ye compares the nervous cells to a tree. The branches of the nervous cells are called dendrites. The dendrites are responsible for the input of nervous impulses from other neurons. The trunk of the nervous cells is called an axon. The axon is responsible for transmitting the nervous impulses to the next nervous cell.

Neuron

“If you want to regenerate an axon to repair an injury, you have to take care of the other end, too”, reports Ye. Even though this axon-dendrite separation of the neuron is considered to be a doctrine among researchers, the mechanism that regulates and maintains their individual functionality is not yet fully understood. During the growth of the human body, the nervous system develops rapidly. However, nervous cells do not divide and replicate. Precedent studies have shown that when a nervous cell reaches its adult form, it no longer has the ability to grow or replicate, thus, any damage caused by neurodegenerative disorders or injury is permanent.

The current study reveals the bi-modal nature of nervous cells and explains how an enzyme, specifically a kinase, can have a different effect on the two parts of the cell. The growth effect that the kinase has on the axon is opposite to the growth impairment that the same kinase has on the dendrites. During their study, the researchers were able to identify the genes that are responsible for this effect. The reason why axon studies are easier than studies performed on dendrites is a technical reason: under the microscope, axons are easier to track and study. Ye’s research team managed to circumvent this technical difficulty by using Drosophila models. In order to study both the axon and dendrites, they labeled them both and observed the effects of various genetic mutations induced on genes shared between humans and Drosophila flies.

One gene that is common between humans and Drosophila flies is known as MAP3K12, which is responsible for coding a protein named DLK (Dual Leucine-Zipper Kinase). The DLK protein is responsible for the growth of the axons. According to the study, longer axons meant higher values of DLK. The nervous cells that had no DLK present showed no regenerative capabilities after injury. On the other hand, high values of DLK also meant that dendrites were less developed. “If we use this kinase, DLK, as a drug target for axon growth, we’ll have to figure out a way to block its effect on dendrites”, concludes professor Ye.

Lifestyle Changes Will Reduce Heart Disease and Mortality

The newest research led by scientists from Johns Hopkins reveals that there is a significant connection between the health of the heart and several lifestyle habits. Their study brings more evidence to support key factors in a patient’s lifestyle, such as a normal weight, a Mediterranean-like diet, regular physical exercise and not smoking. The study was published in the journal American Journal of Epidemiology at the start of this week.

The research team discovered that these 4 lifestyle habits protect the patients against the build-up of calcium in the arteries and against coronary heart disease. Furthermore, the paper reveals that the mortality of patients that follow these lifestyle factors was significantly decreased, by up to 80% over 8 years. “To our knowledge, this is the first study to find a protective association between low-risk lifestyle factors and early signs of vascular disease, coronary heart disease and death, in a single longitudinal evaluation”, reported the lead author of the study, Haitham Ahmed, an internal medicine resident within the Johns Hopkins.

The data of approximately 6,200 patients between the ages of 44 and 84, was evaluated. Patients of African-American, Hispanic, Chinese and Caucasian descend were included in the study and were followed for approximately 7.6 years. According to Ahmed, the patients who followed the healthy habits mentioned earlier showed a decrease in mortality of approximately 80% over the follow-up period. The patients, who were already participating in the MESA (Multi-Ethnic Study of Atherosclerosis) study, were recruited from 6 academic medical centers from the United States, with the condition that they had not been diagnosed with any cardiovascular disease prior to their enrollment in the study.

AHA Recommendations

The participants went through a coronary calcium screening, through CT (Computer Tomography), at the time they enrolled. Calcium deposits in the coronary arteries have been shown to contribute to the overall rate of heart attacks. The research team evaluated the patients periodically, assessing whether or not the participants suffered from chest pains, heart attacks or cardiac arrests during the period of the study, whilst also evaluating the death rate of the patients due to coronary heart disease. Each participant was classified according to a score ranging between 0 and 4, where 0 meant the least healthy lifestyle and 4 mean the healthiest lifestyle. The factors taken into consideration for this classification were diet, BMI (Body-Mass Index), regular physical exercise and smoking status. Out of 129 participants, only 3 patients were classified as having the healthiest lifestyle.

According to professor Roger Blumenthal, who is a cardiologist and the senior author of the study, the most important lifestyle factor contributing to the high risk of coronary heart disease is smoking. According to professor Blumenthal, the smokers who adopted the other 3 lifestyle habits showed a lower survival rate over the 7.6 years, compared to the non-smokers that were obese and even sedentary. Blumenthal and the research team strongly suggest that people follow the recommendations made by the AHA (American Heart Association). These recommendations include quitting smoking, a BMI < 25, regular physical activity and a balanced diet rich in fruits, vegetables and fish.

The research team affirms that their study does not only show the importance of these lifestyle habits against the risk of heart disease, but also shows that these lifestyle factors can reduce the overall mortality of patients in general. Ahmed concluded that even though there are certain risk factors that cannot be altered, such as family heritage, the controllable risk factors should be eliminated or reduced as much as possible.

Better Understanding of Tumor Growth

A new paper published by a research team from the PUPSMD (Plymouth Unverisity Peninsula Schools of Medicine and Dentistry), in the United Kingdom, reveals that if a specific tumor suppressing protein is lost, the result leads to an abnormal proliferation of nervous cells, thus leading to the development of tumors in both the central and peripheral nervous systems. The paper was published at the end of last week, in the journal Brain.

According to the research team there are numerous tumor suppressing proteins in the human cells. The loss of a specific tumor suppressing protein, called “Merlin” (also known as Neurofibromin-2 or schwannomin), causes the development of tumors in several types of cells that make up the nervous system. Each cell contains two copies of this tumor suppressing protein. One of the copies is inherited from the paternal chromosome, while the other is inherited from the maternal chromosome. Researchers say that there are two possible scenarios for the loss of “Merlin”. The first way the copies can be lost is by an accidental loss of both copies from a single cell. This loss could be the cause  for sporadic nervous tumors. The second process involves the inheritance of one abnormal copy of the tumor suppressing protein, and the loss of the healthy copy throughout one’s life. This loss causes the onset of NF2 (Neurofibromatosis type 2).

schwann-cell

Both pathways leading to the loss of the “Merlin” protein cause the development of tumors from myelinating Schwann cells. These are the cells that create the myelin sheath around the axons of both motor and sensory neurons. The tumors derived from Schwann cells are called schwannomas. However, the loss of the tumor suppressor can also lead to tumors forming from other cells from the nervous system, such as the cells responsible for the lining of the brain’s ventricular system and the spinal cord, known as ependymal cells.

Even though schwannomas are mostly benign (only 1% of schwannomas turn malignant) and have a slow growth rate, they occur frequently. Usually, a patient has more than one tumor, which eventually leads to hearing impairment, disability and even death. There have been reported cases of patients with more than 20 separate tumors at the same time. There is no known treatment for schwannomas, except for repeated surgical interventions and single-tumor targeted radiotherapy. Both treatment schemes are very unlikely to fully remove the cancerous tissue.

In their current study, researchers investigated the mechanism through which the loss of Sox10, another protein, causes the development of tumors. The Sox10 protein has been reported to play a major part in the growth of Schwann Cells, however, this is the first study that reveals its implication in the growth of schwannomas. Due to their understanding of the process, the researchers open a new path for future cancer therapies that might provide a more effective alternative to the already existing treatment plans.

Professor David Parkinson is the leader of the research team, comprised of scientists from PUPSMD, SUNY (State University of New York) and FAU (Friedrich-Alexander-Universität Erlangen-Nürnberg). “We have for the first time shown that human schwannoma cells have reduced expression of Sox10 protein and messenger RNA. By identifying this correlation and gaining an understanding of the mechanism of this process, we hope that drug-based therapies may in time be created and introduced that will reduce or negate the need for multiple surgery or radiotherapy”, reported Parkinson as a conclusion.

One in Five U.S. Children Suffers from a Mental Disorder

According to a new federal report, approximately 1 out of 5 American children aged under 17 can be diagnosed with a mental disorder, in a given year. The report was published last Thursday, representing the first comprehensive study done by the government agency in relation to the mental disorders that affect American children. The report, which was conducted by the United States CDC (Centers for Disease Control and Prevention), one of the major operating components of the Department of Health and Human Services,  is mainly focused on 6 areas of diagnostic:

• ADHD, or attention deficit-hyperactivity disorder,
• Tourette syndrome,
• behavioral and conduct disorders,
• anxiety and mood disorders,
• autistic spectrum disorders,
• and disorders caused substance abuse.

Prevalence Chart

According to the report, ADHD the most commonly diagnosed mental disorder in children and adolescents. Circa 6.8% of children between the ages of 3 and 17 are currently diagnosed with a form of ADHD. Symptoms for the disorder include the difficulty of staying focused, difficulty of behavioral control and hyperactivity. The other areas of diagnostic show smaller percentages of occurrence. Approximately 3.5% of children aged between 3 and 17 are diagnosed with conduct or behavioral disorders. Symptoms include the difficulty of learning, unexplained by intellectual or health problems, the difficulty to create and keep a steady relationship with others and different behavioral types that wouldn’t normally occur in normal circumstances. Anxiety is diagnosed in almost 3% of children, while approximately 2.1% suffer from depression. 1.1% of the children are diagnosed with autism, a disorder defined by diminished social interaction and communication skills, and by restricted and repetitive behavioral patterns. Less than 0.5% of children suffer from Tourrette syndrome. Symptoms of Tourette’s include multiple physical and vocal tics.

The report notes that 4.7% of children and teenagers abused illegal drugs during the previous year, 4.2% abused alcohol and circa 2.8% were regular cigarette smokers, while also showing the differences in mental disorder occurrence classified by gender. According to Ruth Perou, the  leader of the study team, girls are less likely to suffer from mental disorders. Specifically, boys are more liable to develop ADHD, autistic spectrum disorders, Tourette’s, anxiety and behavioral problems, and have and increased probability of becoming regular cigarette smokers. On the other hand, girls have an increased probability of becoming alcohol abusers and to suffer from alcohol-related disorders.

Even though this is the first time CDC has compiled a report regarding the prevalence estimates of the most common mental disorders, the agency has done intensive and comprehensive research through multiple population surveys. According to Perou, the prevalence of mental disorders in increasing. The highest prevalence increase was observed in autistic spectrum disorders and in attention deficit-hyperactivity disorders. “We don’t know if it’s due to greater awareness, or if these conditions actually are going up”, said Perou. As a conclusion, Perou reports that the CDC will continue to monitor the prevalence of mental disorders in children due to the fact that an early diagnose can have a great impact on the lives of the children and their families.

Novel Inflammation Pathway

Inflammation is an essential process that occurs in the organism. It is responsible for the protection of the body, through the destruction of harmful stimuli, such as bacteria and viruses, while also removing damaged or dead cells. However, if the process is either chronic or incorrectly controlled, it is responsible for various diseases, such as Chron’s disease, rheumatoid arthritis, asthma, tuberculosis, etc. Chronic inflammation can also lead to sepsis, which is a potentially fatal immune reaction that occurs when the inflammation is triggered throughout the whole organism. The study is led by professor Luke O’Neill, from the TCD (Trinity College Dublin) and it was recently published in the journal Nature.

A research team from the UCD (University College Dublin), in Ireland, reveals a novel signal that is a trigger for the inflammatory response against bacterial infections. In their studies they also managed to block this newly discovered signal in laboratory animal models. According to the researchers involved, the presence of bacteria in the organism triggers the macrophages, which change their energy burning pattern. Macrophages are immune cells that ingest diseased, dead cells or foreign microorganisms. The change in their burning pattern leads to the accumulation of succinate in the cells, which subsequently triggers a series of biochemical events that stimulates the onset of inflammation.

Chronic Inflammation

One part of the biochemical events involves a small molecule known as HIF-1a (hypoxia-induced factor 1a). This molecule is responsible for the organism’s adaptation to low oxygen situations. Professor Cormac Taylor, one of the researchers of the study, explains that, “when you go to high altitude, this factor gets expressed in cells and that helps to increase the number of red blood cells in your blood, so you can adapt to the lower oxygen”. However, that is not the sole function of HIF-1a. According to professor Taylor, the molecule’s pathway also activates during stress. Previous studies show that the activation of HIF-1a is present in inflammatory bowel disease. Together with Dr Eoin Cummins, professor Taylor discovered that when macrophages sense a threat posed by bacteria, they build-up succinate, which causes the HIF-1a molecule to switch ‘on’ the IL-1 (interleukin-1) gene. IL-1 is a very potent  pro-inflammatory gene which contributes to the onset of the inflammatory process.

The current study reveals the important connection between the macrophages’ energy burning processes that occur during the immune process and the onset of inflammation. Moreover, the research team also shows that the activity of the succinate/HIF-1a was partially blocked by a drug that’s currently being used to treat epilepsy. The effect was achieved in a laboratory animal model with sepsis. “It’s a big emerging area, the links between metabolism, or energy burning, and inflammation in disease”, concluded professor Taylor.

Novel Anti-Cocaine Vaccine

Scientists from the Weill Cornell Medical College, in New York, the United States, reveal the test results of their newest anti-cocaine vaccine. The vaccine was tested on primates and thus came one step closer to the clinical trials on humans. Their paper was published in the online journal Neuropsychopharmacology earlier this week. The team demonstrated the effectiveness of their vaccine through a radiological technique that showed that the drug was stopped from entering the brain.

Dr Ronald Crystal, the main author of the study reports that “The vaccine eats up the cocaine in the blood like a little Pac-man before it can reach the brain”, adding that he believes that the new vaccine offers a win-win strategy for cocaine abusing patients. Estimates show that there are approximately 1.5 million users in the United States alone that are trying to give up their addiction. Dr Crystal expects the vaccine to enter human clinical trials within the upcoming year.

Cocaine is a compound that is obtained from the coca plant leaves. It is a psychostimulant, an anesthetic and an appetite suppressant. Its effect is obtained through the blocking of the dopamine recycling process from two distinct areas of the brain. These areas are the putamen, found at the base of the forebrain and the caudate nucleus, located within the basal ganglia of the brain. The growth of dopamine levels at the nerve endings it provokes the cocaine high effect. The innovative vaccine developed by the research team uses a combination of a particle that imitates the cocaine structure and parts of the common cold virus.

According to Dr Crystal, the organism responds to the injection of the novel vaccine with an immune response that affects the virus itself and the cocaine-like molecule that is attached to the virus. Thus, the immune system becomes able to treat the cocaine molecule as an intruder. With their new capability, the immune cells can produce antibodies against cocaine immediately after the immune system detects its presence in the organism.

Cocaine

Their first study revealed that the injection of the new vaccine caused the immune system of the mouse models to create an impressive response against the virus contained within. Moreover, the mouse models that received both the vaccine and cocaine were observed to be significantly less hyperactive, in comparison to mouse models which received cocaine without the vaccine.

However, in the current study, the research team wanted to precisely determine the effectiveness of the anti-cocaine vaccine in primates. The organism of primates is considered to be much closer to that of humans, in comparison to mice. In order to solve this puzzle, researchers created a tool that measures the amount of cocaine that is attached to the dopamine transporter. This is a membrane protein that pumps dopamine from the synapse to the cytosol. When cocaine reaches the brain, it binds to the dopamine transporter, thus blocking its ability to recycle synaptic dopamine. This further leads to the drug high effect.

Researchers used an isotope tracer in order to track the dopamine transporters. Through the use of PET (Positron Emission Tomography), researchers were able to observe the activity of these transporters and measure the amount of isotope tracer that was attached to the transporter, both in the presence and absence of cocaine. The first assessment showed little to no difference between the presence of the tracer in vaccinated and non-vaccinated primates. However, when cocaine was given to the tested primates, the activity of the tracer dropped significantly in the non-vaccinated group. These results reveal that in the non-vaccinated group, cocaine displaced the isotope tracer.

Precedent studies have shown that it takes a minimum of 47% of the transporter to be occupied with cocaine before any drug high effects occur in human patients. Dr Crystal’s study shows that their novel vaccine causes the dopamine receptor to be occupied with cocaine by less than 20%. “This is a direct demonstration in a large animal, using nuclear medicine technology, that we can reduce the amount of cocaine that reaches the brain sufficiently so that it is below the threshold by which you get the high”, affirmed Dr Crystal.

The current results of the study show that the effect of the vaccine lasts for as many as 7 weeks on primates and approximately 4 months on mice. Dr Crystal concluded that if the vaccine will pass the human clinical trials, it is very probable that patients will need booster shots. However, at the current time, the amount of booster shots needed and the frequency of administration is unknown.

Treating Neurodegenerative Diseases

Scientists from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, at the UCLA (University of California, Los Angeles) managed to create a laboratory model of the disorder named ataxia telangiectasia, a very rare genetic disease, through the use of induced pluripotent stem cells (iPSC). Their results show that several new drugs have positive effects, thus opening new doors for future treatment plans against neurodegenerative disorders. The induce pluripotent stem cells were derived from the skin of the patient, rather than from embryos. The study was published in the online journal Nature Communications, prior to its publication in the printed version of the journal.

Doctors Richard Gatti & Peiyee Lee are the leaders of the study. Their team managed to harvest iPSCs and use them to create the disease-in-a-dish model of the disorder known as ataxia telangiectasia. This technique uses the ability of the stem cells to regenerate and differentiate in a Petri dish. Basically, this allows researchers to study the disease in the laboratory, being able to test various drugs on the cells.

Ataxia telangiectasia (A-T), a disease also known as the Louis-Bar syndrome, is a neurodegenerative disease that  causes severe disability for patients. The word “ataxia” refers to the poor muscular coordination, whilst the word “telangiectasia” refers to the small dilated blood vessels found near the mucous membranes or the skin of the patient. Both of these symptoms are pathognomonic signs for the disease. The parts of the organism that are most likely to be affected are the brain and the immune system. Ataxia telangiectasia also affects the DNA, inhibiting its repairing capability, thus increasing the risk for the onset of cancer. The loss of function in the cerebellum leads to the difficulties in muscular coordination and movement. Due to their weakened immune system, patients with A-T are most likely to suffer from frequent infections.

Neurodegeneration

The gene responsible for the disease, named ATM (ataxia telangiectasia mutated), is found on the long arm of chromosome 11 and is responsible for the repairing of damaged DNA. The development of a disease-in-a-dish model of the disease was critical due to the fact that the disease is different in laboratory animals and humans. The animal models of the disease do not suffer from cerebellum damage, thus the coordination and movement difficulties cannot be studied. The newly developed model also allows researchers to test new drugs.

Professor Lee and his colleagues used the iPSCs to create neural cells that were developed from the skin cells of patients with specific types of genetic mutations. In their lab tests, scientists managed to model the cell’s incapability to repair the damaged DNA due to the absence of the ATM proteins. The disease-in-a-dish model also allowed the research team to test SMRT (small molecule read-through), a new drug that would increase the activity of the ATM protein. According to professor Lee, patients who show even the slightest activity of the ATM protein suffer from a less severe form of the disease. “This makes our discovery promising, because even a small increase in the ATM activity induced by the SMRT drug can potentially translate to positive effects for patients, slowing disease progression and hopefully improving their quality of life”, Lee added.

The results of the study reveal that the tested SMRT drug could have a beneficial effect on A-T patients, through the improvement of the function of their immune system. Moreover, the iPSCs that were combined with the SMRT drug might be invaluable for identifying and understanding the onset and progression of A-T. The research team suggests that the SMRT drug could be effective against other neurodegenerative disorders as well.

Shortening of Telomeres Linked to Muscular Dystrophy Onset

A recent study that was published in the journal Nature Structural & Molecular Biology reveals that the shortening of the telomeres (a process that is linked to the aging process of the organism) is associated with an increased gene expression associated with FSHD (Facioscapulohumeral muscular dystrophy). FSHD, also known as Landouzy-Dejerine, is an autosomal dominant inherited form of muscular dystrophy which affects the skeletal muscles of the face (facio), scapula (scapulo) and upper arms (humeral). Symptoms of the disease appear by the age of 20, even though other muscular dystrophies show symptoms earlier during childhood. Furthermore, only 1 in less than 20,000 patients who carry the genetic mutations responsible for FSHD, will eventually develop the disease.

The main author of the study and the leader of the research team from the UTSW (University of Texas Southwestern) Medical Center, in the United States, professor Woodring Wright, affirms that these results could explain the late onset of the disease and the fact that only a very small number of patients develop the disease, even if they are carriers for the mutated genes.

Muscular Dystrophy

Telomeres are regions of repetitive sequences of nucleotides found at the end of each chromatid. Their role is to protect the chromosomes from either external deterioration or  fusion with other chromosomes. The genes found in the proximity of the telomeres are usually inactive. With age, the telomeres shorten, thus affecting the expression of the proximity genes. This effect is currently known as TPE (telomere position effect). Due to the fact that the gene responsible for the development of FSHD is in the vicinity of a telomere, it is usually inactive. However, due to the shortening of the telomeres, the gene, named DUX4, changes its expression.

Professor Wright and his research team managed to clone the muscle precursor cells from patients suffering from FSHD and their healthy siblings. They discovered that there was a difference between the lengths of the telomeres. According to the results of the study, the expression of the DUX4 gene dramatically increased as the length of the telomeres decreased. This suggests that if a patient either has telomeres that shorten at a slower rate, or has longer telomeres, will most likely never develop the disease, even if they carry the DUX4 gene.

The shortening of the telomeres could also explain why the disease has such a late onset. The research team from UTSW are already planning future studies that will focus on the link between FSHD onset and telomere length. DUX4 is rather close to the telomeres, being only 25 to 60 kilobases away, however, scientists also discovered that the shortening of the telomeres affects the FRG2 gene as well, found at 100 kilobases away. This discovery is an indication that the telomere position effect could affect many other genes. Researchers affirm that in the near future, physicians will take the length of the telomeres into consideration when diagnosing these muscular dystrophies and other genetic disorders linked to the shortening of telomeres.