Stem Cells Poised to Self-Destruct for the Good of the Embryo

Embryonic stem cells -- those revered cells that give rise to every cell type in the body -- just got another badge of honor. If they suffer damage that makes them a threat to the developing embryo, they swiftly fall on their swords for the greater good, according to a study published online May 3, 2012 in the journal Molecular Cell.

This is an image depicting active Bax (red) located at Golgi of human embryonic stem cells. Nuclei are stained in blue [Credit: Deshmukh Lab, UNC-Chapel Hill]

The finding offers a new glimpse into the private lives of stem cells that could help scientists use them to grow new neurons or other cells to replace those that have been lost in patients with Parkinson's and other diseases. "Despite the huge potential of stem cells for therapeutic use, very few people have actually investigated their basic biology," said study senior researcher Mohanish Deshmukh, PhD, professor of cell and developmental biology at the University of North Carolina at Chapel Hill. "These results could have significant implications from a therapeutic perspective."

Of all the important things our bodies' cells do, staying alive is clearly key. But a cell's ability to die when something goes wrong is equally critical. For example, a faulty self-destruct button is one factor that allows cancer cells to proliferate unchecked and cause tumors.

Deshmukh and his colleagues discovered stem cells are extremely sensitive to DNA damage, which can be caused by factors like chemicals, radiation or viruses. The experiment showed that virtually 100 percent of human embryonic stem cells treated with a DNA-damaging drug killed themselves within 5 hours, as compared to 24 hours for other types of cells. "That's an incredibly rapid rate of death," said Deshmukh, who also is a member of the UNC Neuroscience Center and Lineberger Comprehensive Cancer Center.

The hair-trigger suicidal response is an important adaptation for embryonic stem cells, said the UNC School of Medicine researcher, because a slower response could allow DNA damage to proliferate and harm the embryo. "Mutations that develop in these cells could be catastrophic for the developing organism, so it would make sense for these cells to be rapidly eliminated."

The key to the stem cells' quick response is that they pre-activate a critical protein called Bax, the researchers found. In most cells, Bax is is kept in an inactive form, waiting for a long chain of events to rouse it into action if the cell becomes damaged enough to kill itself. In human embryonic stem cells, the team found Bax standing at attention in its active form in the Golgi apparatus, a part of the cell that processes and modifies proteins.

"What these cells do is very clever," said Deshmukh. "They have activated Bax, but they've also parked it in a safe little compartment -- the Golgi." If the cell detects DNA damage, Bax zips over to the mitochondrion (the cell's power plant), where it signals other proteins to shut the cell down.

It's like starting a 100-yard race at the 80-yard line, said Deshmukh. You're guaranteed to get to the finish line first because you did most of the work before the race began. However, there are built-in safeguards against a hair trigger activation of death. Pre-activated Bax is housed in the Golgi keeping the protein from accidentally triggering cell death when it's not warranted.

This extreme sensitivity to DNA damage lasts only a few days during early development. After the embryonic stem cells begin differentiating into early progenitors that give rise to specific cell types (like heart cells or skin cells), Bax reverts to its inactive state.

UNC Co-first authors of this study are -- Raluca Dumitru and Vivian Gama. Other UNC Co-authors include B. Matthew Fagan, Jacquelyn J Bower, Vijay Swahari and Larysa H Pevny. The study was funded by grants from the National Institutes of Health (National Institute of General Medical Sciences) and UNC's University Cancer Research Fund.

Source: University of North Carolina at Chapel Hill School of Medicine [May 03, 2012]

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Biologists a Step Nearer to Solving the Parkinson's Conundrum

Scientists at the University of York have made a significant step forward in isolating the cause of Parkinson's disease in younger adults. 

Parkinson's disease occurs when some nerve cells in a part of the brain called the substantia nigra die or become impaired. Normally, these cells produce dopamine - a vital chemical that allows smooth, coordinated function of the body's muscles and movements [Credit: iStockphoto/Martí Sáiz]

Research by a team in the University's Department of Biology found evidence that movement disorders, including tremor and slowness of movement (bradykinesia), associated with Parkinson's disease (PD) may be due to a defect in energy production in the nervous system. The advance may help to identify young adults who may be susceptible to the disease. 

Parkinson's, the second most common form of neurodegenerative disease, principally affects people aged over 60, but some forms -- known as juvenile PD -- usually start in the 30-40 age group. One in 20 people diagnosed with Parkinson's are under 40 and such early onset PD is often inherited. Previous research has identified the genes which cause the disease and found them to be linked in a common pathway to failure of the mitochondria -- the power source within each cell. 

In the latest research, part-funded by leading research charity Parkinson's UK and published in Human Molecular Genetics, scientists at York studied the effect that parkin, one of the genes which cause juvenile PD, has on the larva of the fruit fly, Drosophila. 

They discovered that parkin faithfully models the locomotory defects of PD with a marked reduction in speed, and slower muscle contractions, reminiscent of bradykinesia. 

Dr Chris Elliott, who led the study, said: "Our experimental evidence confirmed that this was due to a defect in the nervous system. This was important because previous work had suggested a big impact on the muscles, but PD is associated with neuronal failure." 

The research team, which included undergraduate and postgraduate students, found that oxygen consumption and the production of ATP (the chief supply of energy inside cells) were drastically reduced. In response, lactate was increased. 

The researchers also discovered that parkin larvae showed oxidative stress due to high levels of reactive oxygen species (ROS; also known as free radicals, such as hydrogen peroxide) which have been suggested as a key component of PD. The study suggested that relieving the ROS had only a marginal effect on mitigating slowed locomotion. 

Dr Elliott added: "These findings show drastic failure in energy production by parkin larvae, and suggest that biochemicals related to lactate may be worth investigating as biomarkers for the progress of PD. 

"We believe that the larval bradykinesia is a consequence of neuronal energy deficit, which leads to failure in neural communication. Oxidative stress is a consequence, rather than cause, of PD." 

Dr Kieran Breen, Director of Research and Innovation at Parkinson's UK, comments: "This study shows just how vital models like the fruit fly are in helping us understand what happens to the nerve cells that are affected in Parkinson's. 

"We already knew that mitochondria were important in Parkinson's but this research suggests that mitochondrial problems may be the root cause of the problems that lead to nerve cell death. 

"So finding ways to protect and enhance the mitochondria may be the key to treatments that can slow or even stop Parkinson's in its tracks." 

Source: University of York [January 16, 2012]

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Tapping the brain orchestra

Researchers at the Norwegian University of Life Sciences (UMB) and Forschungszentrum Jülich in Germany have developed a new method for detailed analyses of electrical activity in the brain. The method, recently published in Neuron, can help doctors and researchers to better interpret brain cell signals. In turn, this may lead to considerable steps forward in terms of interpreting for example EEG measurements, making diagnoses and treatment of various brain illnesses. 

A forest of neurons [Credit: Hermann Cuntz]

Researchers and doctors have been measuring and interpreting electrical activity generated by brain cells since 1875. Doctors have over the years acquired considerable practical skills in relating signal shapes to different brain illnesses such as epilepsy. However, doctors have so far had little knowledge on how these signals are formed in the network of nerve cells. 

"Based on methods from physics, mathematics and informatics, as well as computational power from the Stallo supercomputer in Tromsø, we have developed detailed mathematical models revealing the connection between nerve cell activity and the electrical signal recorded by an electrode," says Professor Gaute Einevoll at the Department of Mathematical Sciences and Technology (IMT) at UMB. 

Microphone in a crowd 

The problem of interpreting electrical signals measured by electrodes in the brain is similar to that of interpreting sound signals measures by a microphone in a crowd of people. Just like people sometimes all talk at once, nerve cells are also sending signals "on top of each other". 

The electrode records the sounds from the whole orchestra of nerve cells surrounding it and there are numerous contributors. One cubic millimetre can contain as many as 100,000 nerve cells. 

Treble and bass 

Similar to bass and treble in a soundtrack, high and low frequency electrical signals are distinguished in the brain. 

"This project has focused on the bass - the low frequency signals called "local field potential" or simply LFP. We have found that if nerve cells are babbling randomly on top of each other and out of sync, the electrode's reach is narrow so that it can only receive signals from nerve cells less than about 0.3 millimetres away. However, when nerve cells are speaking simultaneously and in sync, the range can be much wider," Einevoll says. 

Large treatment potential 

Better understanding of the electrical brain signals may directly influence diagnosing and treatment of illnesses such as epilepsy. 

"Electrodes are already being used to measure brain cell activity related to seizures in epilepsy patients, as well as planning surgical procedures. In the future, LFP signals measured by implanted electrodes could detect an impending epilepsy seizure and stop it by injecting a suitable electrical current," Einevoll says. 

"A similar technique is being used on many Parkinson's patients, who have had electrodes surgically implanted to prevent trembling," Researcher Klas Pettersen at UMB adds. 

Einevoll and Pettersen also outline treatment of patients paralysed by spinal cord fracture as another potential area where the method can be used. 

"When a patient is paralysed, nerve cells in the cerebral cortex continue to send out signals, but the signals do not reach the muscles, and the patient is thus unable to move arms or legs. By monitoring the right nerve cells and forwarding these signals to for example a robot arm, the patient may be able to steer by his or her thoughts alone," Einevoll says. 

The Computational Neuroscience Group at UMB has already established contacts with clinical research groups in the USA and Europe for further research on using the approach in patient treatment.  

Author: Torunn Moe | Source: Norwegian University of Life Sciences [December 08, 2011]

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People with Parkinson's disease more likely to have leg restlessness than restless leg syndrome

People with Parkinson's disease may be more likely to have a movement disorder called leg motor restlessness, but not true restless legs syndrome as previous studies have suggested, according to a study published in the Nov. 9, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology. 

Restless legs syndrome is a sleep and movement disorder. People with the disorder have the urge to move their legs to stop uncomfortable sensations. The urge occurs when the person is at rest, in the evening, and is temporarily relieved by movement. In leg motor restlessness, people also have the urge to move their legs, but it is either not worse when they are at rest or during the evening or it does not go away when they move their legs. 

Because restless legs syndrome and Parkinson's disease both respond to the drug dopamine, researchers have looked for connections between the two disorders. Some studies have shown that people with Parkinson's disease are more likely also to have restless legs syndrome than people who don't have Parkinson's disease. But those studies have looked at people with advanced cases of Parkinson's who have taken dopamine drugs for many years. 

The current study is the first to look at the issue in people who were recently diagnosed with Parkinson's disease and have not yet taken any dopamine drugs. The Norwegian study compared 200 people with early Parkinson's disease to 173 people of similar ages who did not have Parkinson's disease. 

The study found that restless legs syndrome was not significantly more common in people with Parkinson's disease than it was in those without the disease. But people with Parkinson's were nearly three times more likely to have leg motor restlessness than those without Parkinson's. A total of 26 people with Parkinson's disease and 10 people without the disease had leg motor restlessness. 

"This finding could possibly be because people who have not yet taken dopamine for their Parkinson's disease have a dopamine deficiency in their brains, which is similar to when people develop motor restlessness after taking antipsychotic drugs that block dopamine in the brain," said study author Michaela D. Gjerstad, PhD, of Stavanger University Hospital in Norway and a Fellow of the American Academy of Neurology. 

John Morgan, MD, PhD, of Georgia Health Sciences University in Augusta, who wrote an editorial regarding the study, said, "Time will tell whether the majority of these people with leg motor restlessness will go on to develop restless legs syndrome, or whether the restlessness improves after they start taking dopamine drugs. Further study of this group of people will be quite interesting." 

Source: American Academy of Neurology [November 09, 2011]

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Brain stimulator shown to reduce 'untreatable' epileptic seizures

Brain stimulation, already approved by the U.S. Food and Drug Administration for the treatment of Parkinson's disease and essential tremor, has now been shown to offer significant relief to patients with intractable seizures for whom drugs and other treatments have not worked. 

This is the major finding of a first-of-its-kind study of responsive electric brain stimulation in adults with "medically refractory," or hard to treat, epilepsy. 

The NeuroPace Responsive Neurostimulation (RNS) System consists of a miniaturized, implanted computer which can detect seizures from electrodes implanted into or on the surface of the brain and deliver an electrical pulse to stop them. 

Henry Ford Hospital was the only site in Michigan to participate in this multicenter investigation, which was based in California. The study is published in the current issue of Neurology. 

"For the third of people who have tried two or three medications for their epilepsy, but are still having seizures, the standard of care is removing the abnormal part of the brain that is causing seizures. Over 50 percent of patients undergoing surgical removal of brain tissue causing seizures will be cured of their epilepsy," says Jason M. Schwalb, M.D., Director, Movement Disorder and Behavioral Neurosurgery at Henry Ford Health System. 

"However, there are people who are not candidates for this type of surgery because of potential side effects. Until now, we have not had great treatment options. The RNS system is an attractive option for these patients, especially since it is reversible." 

A total of 191 adults, ages 18 to 70, whose disabling epileptic seizures had not been controlled by at least two medications, were chosen. They were studied at 32 medical sites throughout the U.S. for three years, beginning in late 2005. 

All patients were implanted with electric leads attached to one or two seizure focal points in their brains. Their abnormal brain activity was recorded for a month, and then they were chosen at random either to receive electric stimulation or to be given "sham," or no treatment. 

The researchers found: 

• The 97 patients who were treated with the RNS system had 37.9 percent fewer seizures than before surgery. Those 94 patients in the sham, or untreated group, had only 17.3 fewer seizures than before surgery. 

• When those in the sham group had the RNS system turned on, seizures were significantly reduced. 

• There was no difference between the two groups in the number of adverse events associated with the treatment. 

• The effects of the treatment led to significant improvements in patients' quality of life. (Medically refractory epilepsy patients with frequent seizures are at risk of depression, suicidal thoughts and actions, memory loss, and SUDEP, or sudden unexplained death in epilepsy.)  

Source: Henry Ford Health System [November 08, 2011]

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Study suggests increased risk of schizophrenia in heavy methamphetamine users

In the first worldwide study of its kind, scientists from Toronto's Centre for Addiction and Mental Health (CAMH) found evidence that heavy methamphetamine users might have a higher risk of developing schizophrenia. This finding was based on a large study comparing the risk among methamphetamine users not only to a group that did not use drugs, but also to heavy users of other drugs. 

The report will be published online on Nov. 8, 2011, at AJP in Advance, the advance edition of the American Journal of Psychiatry, the official journal of the American Psychiatric Association. 

Methamphetamine and other amphetamine-type stimulants are the second most common type of illicit drug used worldwide. 

"We found that people hospitalized for methamphetamine dependence who did not have a diagnosis of schizophrenia or psychotic symptoms at the start of our study period had an approximately 1.5 to 3.0-fold risk of subsequently being diagnosed with schizophrenia, compared with groups of patients who used cocaine, alcohol or opioid drugs," says Dr. Russ Callaghan, the CAMH scientist who led the study. Dr. Callaghan also found that the increased risk of schizophrenia in methamphetamine users was similar to that of heavy users of cannabis. 

To establish this association, the researchers examined California hospital records of patients admitted between 1990 and 2000 with diagnosis of dependence or abuse for several major abused drugs: methamphetamine, cannabis, alcohol, cocaine or opioids. They also included a control group of patients with appendicitis and no drug use. The methamphetamine group had 42,412 cases, while cannabis had 23,335. 

Records were excluded if patients were dependent on more than one drug or had a diagnosis of schizophrenia or drug-induced psychosis during their initial hospitalization. Readmission records within California hospitals were analyzed for up to 10 years after the initial admission. The researchers then identified patients who were readmitted with a schizophrenia diagnosis in each drug group. 

There has been a longstanding debate as to whether there is a connection between methamphetamine use and schizophrenia. Many Japanese clinicians have long believed that methamphetamine might cause a schizophrenia-like illness, based on their observations of high rates of psychosis among methamphetamine users admitted to psychiatric hospitals. However, they lacked long-term follow-up studies of methamphetamine users initially free of psychosis. In North America, this link has mostly been discounted, as psychiatrists believed that the psychosis was already present and undiagnosed in these methamphetamine users. 

"We really do not understand how these drugs might increase schizophrenia risk," says Dr. Stephen Kish, senior scientist and head of CAMH's Human Brain Laboratory. "Perhaps repeated use of methamphetamine and cannabis in some susceptible individuals can trigger latent schizophrenia by sensitizing the brain to dopamine, a brain chemical thought to be associated with psychosis." Dr. Kish also cautions that the findings do not apply to patients who take much lower and controlled doses of amphetamines or cannabis for medical purposes. 

Since this is the first such study showing this potential link, the researchers emphasize that the results need to be confirmed in additional research involving long-term follow-up studies of methamphetamine users. 

"We hope that understanding the nature of the drug addiction-schizophrenia relationship will help in developing better therapies for both conditions," says Dr. Callaghan. 

In an earlier study using California hospital records, the researchers found evidence for a possible association between heavy methamphetamine use and Parkinson's disease. 

Source: Centre for Addiction and Mental Health [November 08, 2011]

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Brain parasite directly alters brain chemistry

A research group from the University of Leeds has shown that infection by the brain parasite Toxoplasma gondii, found in 10-20 per cent of the UK's population, directly affects the production of dopamine, a key chemical messenger in the brain. Their findings are the first to demonstrate that a parasite found in the brain of mammals can affect dopamine levels. 

Toxoplasma gondii [Credit: Ke Hu and John Murray]

Whilst the work has been carried out with rodents, lead investigator Dr Glenn McConkey of the University's Faculty of Biological Sciences, believes that the findings could ultimately shed new light on treating human neurological disorders that are dopamine-related such as schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease. 

This research may explain how these parasites, remarkably, manipulate rodents' behaviour for their own advantage. Infected mice and rats lose their innate fear of cats, increasing the chances of being caught and eaten, which enables the parasite to return to its main host to complete its life cycle. 

In this study, funded by the Stanley Medical Research Institute and Dunhill Medical Trust, the research team found that the parasite causes production and release of many times the normal amount of dopamine in infected brain cells. 

Dopamine is a natural chemical which relays messages in the brain controlling aspects of movement, cognition and behaviour. It helps control the brain's reward and pleasure centres and regulates emotional responses such as fear. The presence of a certain kind of dopamine receptor is also associated with sensation-seeking, whereas dopamine deficiency in humans results in Parkinson's disease. 

These findings build on earlier studies in which Dr McConkey's group found that the parasite actually encodes the enzyme for producing dopamine in its genome. 

"Based on these analyses, it was clear that T. gondii can orchestrate a significant increase in dopamine production in neural cells," says Dr McConkey. 

"Humans are accidental hosts to T. gondii and the parasite could end up anywhere in the brain, so human symptoms of toxoplasmosis infection may depend on where parasite ends up. This may explain the observed statistical link between incidences of schizophrenia and toxoplasmosis infection." 

Dr McConkey says his next experiments will investigate how the parasite enzyme triggers dopamine production and how this may change behaviour. 

Source: University of Leeds [November 04, 2011]

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