ALS progression linked to increased protein instability

The new study provides evidence that proteins linked to more severe forms of ALS are less stable structurally and more prone to form clusters or aggregates. Mutants of the superoxide dismutase (SOD) protein formed long, rod-shaped aggregates (shown here as red lattice), compared to the compact folded structure of wild-type SOD (purple ribbons). Credit: Image courtesy of the Getzoff and Tainer labs, The Scripps Research Institute.

A new study by scientists from The Scripps Research Institute (TSRI), Lawrence Berkeley National Laboratory (Berkeley Lab) and other institutions suggests a cause of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

"Our work supports a common theme whereby loss of protein stability leads to disease," said John A. Tainer, professor of structural biology at TSRI and senior scientist at Berkeley Lab, who shared senior authorship of the new research with TSRI Professor Elizabeth Getzoff.

Getzoff, Tainer and their colleagues, who focused on the effects of mutations to a gene coding for a protein called superoxide dismutase (SOD), report their findings this week in the online Early Edition of the Proceedings of the National Academy of Sciences. The study provides evidence that those proteins linked to more severe forms of the disease are less stable structurally and more prone to form clusters or aggregates.

"The suggestion here is that strategies for stabilizing SOD proteins could be useful in treating or preventing SOD-linked ALS," said Getzoff.

Striking in the Prime of Life

ALS is notorious for its ability to strike down people in the prime of life. It first leapt into public consciousness when it afflicted baseball star Lou Gehrig, who succumbed to the disease in 1941 at the age of only 38. Recently, the ALS Association's Ice Bucket Challenge has enhanced public awareness of the disease.

ALS kills by destroying muscle-controlling neurons, ultimately including those that control breathing. At any one time, about 10,000 Americans are living with the disease, according to new data from the Centers for Disease Control and Prevention, but it is almost always lethal within several years of the onset of symptoms.

SOD1 mutations, the most studied factors in ALS, are found in about a quarter of hereditary ALS cases and seven percent of ordinary "sporadic" ALS cases. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation. Scientists still don't agree, though, on just how the dozens of different SOD1 mutations all lead to the same disease.

One feature that SOD1-linked forms of ALS do have in common is the appearance of SOD clusters or aggregates in affected motor neurons and their support cells. Aggregates of SOD with other proteins are also found in affected cells, even in ALS cases that are not linked to SOD1 mutations.

In 2003, based on their and others' studies of mutant SOD proteins, Tainer, Getzoff and their colleagues proposed the "framework destabilization" hypothesis. In this view, ALS-linked mutant SOD1 genes all code for structurally unstable forms of the SOD protein. 
Inevitably some of these unstable SOD proteins lose their normal folding enough to expose sticky elements that are normally kept hidden, and they begin to aggregate with one another, faster than neuronal cleanup systems can keep up -- and that accumulating SOD aggregation somehow triggers disease.

Faster Clumping, Worse Disease

In the new study, the Tainer and Getzoff laboratories and their collaborators used advanced biophysical methods to probe how different SOD1 gene mutations in a particular genetic ALS "hotspot" affect SOD protein stability.

To start, they examined how the aggregation dynamics of the best-studied mutant form of SOD, known as SOD G93A, differed from that of non-mutant, "wild-type" SOD. To do this, they developed a method for gradually inducing SOD aggregation, which was measured with an innovative structural imaging system called SAXS (small-angle X-ray scattering) at Berkeley Lab's SIBYLS beamline.

"We could detect differences between the two proteins even before we accelerated the aggregation process," said David S. Shin, a research scientist in Tainer's laboratories at Berkeley Lab and TSRI who continues structural work on SOD at Berkeley.

The G93A SOD aggregated more quickly than wild-type SOD, but more slowly than an SOD mutant called A4V that is associated with a more rapidly progressing form of ALS.

Subsequent experiments with G93A and five other G93 mutants (in which the amino acid glycine at position 93 on the protein is replaced with a different amino acid) revealed that the mutants formed long, rod-shaped aggregates, compared to the compact folded structure of wild-type SOD. The mutant SOD proteins that more quickly formed longer aggregates were again those that corresponded to more rapidly progressing forms of ALS.

What could explain these SOD mutants' diminished stability? Further tests focused on the role of a copper ion that is normally incorporated within the SOD structure and helps stabilize the protein. Using two other techniques, electron-spin resonance (ESR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS), the researchers found that the G93-mutant SODs seemed normal in their ability to take up copper ions, but had a reduced ability to retain copper under mildly stressing conditions -- and this ability was lower for the SOD mutants associated with more severe ALS.

"There were indications that the mutant SODs are more flexible than wild-type SOD, and we think that explains their relative inability to retain the copper ions," said Ashley J. Pratt, the first author of the study, who was a student in the Getzoff laboratory and postdoctoral fellow with Tainer at Berkeley Lab.

Toward New Therapies

In short, the G93-mutant SODs appear to have looser, floppier structures that are more likely to drop their copper ions -- and thus are more likely to misfold and stick together in aggregates.

Along with other researchers in the field, Getzoff and Tainer suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems, stressing and ultimately killing affected neurons.

"Because mutant SODs get bent out of shape more easily," said Getzoff, "they don't hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS."

The researchers also plan to confirm the relationship between structural stability and ALS severity in other SOD mutants.

"If our hypothesis is correct," said Shin, "future therapies to treat SOD-linked ALS need not be tailored to each individual mutation -- they should be applicable to all of them."

Source: The Scripps Research Institute

Read More

Cone snail venom holds promise for medical treatments for cancer, addiction

Professor Frank Marí in the Charles E. Schmidt College of Science at Florida Atlantic University holds a live Conus regius, a particular species of cone snail collected by the Marí group at the Florida Keys. Credit: Professor Anton Oleinik

While considered a delicacy in some parts of the world, snails have found a more intriguing use to scientists and the medical profession offering a plethora of research possibilities. Cone snails are marine mollusks, just as conch, octopi and squid, but they capture their prey using venom. The venom of these marine critters provides leads for detection and possible treatment of some cancers and addictions.

Frank Marí, Ph.D., professor in the Department of Chemistry and Biochemistry in FAU's Charles E. Schmidt College of Science at Florida Atlantic University, has focused his research on cone snail venom and has published a study in the current issue of the Journal of Biological Chemistry.

"The venom produced by these animals immobilizes prey, which can be worms, other snails and fish," said Marí. "The venom is an extraordinary complex mixture of compounds with medicinal properties."

The venom components selectively target cells in the body and make them valuable drug leads and powerful molecular tools for understanding the human body's processes. One class of venom components is the alpha-conotoxins, named so because they target nicotinic receptors that are central to a range of diseases such as Alzheimer's disease, schizophrenia, tobacco addiction and lung cancer.

The venom of a particular species of cone snail, Conus regius, collected by the Marí group at the Florida Keys, is particularly rich in alpha conotoxins. Aldo Franco, Ph.D., who worked in Marí's lab, described more than ten new alpha-conotoxins in his Ph.D. dissertation at FAU. 

Among these, they found RegIIA, a compound that potently blocked the alpha3beta4 nicotinic receptor. This particular receptor when activated can be associated with lung cancer and nicotine addiction.

"We investigated in detail how RegIIA interacts with the alpha3beta4 nicotinic receptors and embarked on engineering new compounds that were more specific toward alpha3beta4 receptors and not other nicotinic receptors," said Marí. "Our aim is to open new avenues for cancer and addiction research inspired on compounds from marine animals."

Cone snails can be found throughout the Florida coast at different depths. Marí and his team regularly collect these animals using SCUBA and sometimes using deep-water submarines.

Source: Florida Atlantic University

Read More

How to sell the drugs of the future

Drugs
Credit: Getty Images

Only a decade ago, basing medical treatment on your DNA seemed like science fiction. Not any more. Thanks in part to the sequencing of the human genome, personalized medicine (PM), a specific course of treatment developed for the individual patient, is now science fact.

PM has already shown its effectiveness in the treatment of cancer, and medical professionals are eager to expand it to treat other chronic diseases. But first patients need to understand how PM can work for them.

Will they buy into it? "Yes -- but only if patients are armed with knowledge about their own disease and understand the relative advantages of PM," says Concordia University marketing professor Lea Prevel Katsanis, the co-author of a new study on the subject, published in the International Journal of Pharmaceutical and Healthcare Marketing. She adds that if patients are going to accept PM, doctor-patient communication is vital.

For the study, Katsanis and her co-author, Anja Hitz, a former John Molson School of Business MBA student and current head of medical compliance and prevention at the Military Hospital in Hamburg, Germany, polled 307 consumers through an online survey. 
They found that knowledge and the relative advantages of PM have the most significant influence on patient acceptance of PM.

"The more a patient knows about how she is being treated, the more likely she is to accept that treatment," says Katsanis. "So it's important to educate consumers on potential benefits and risks associated with PM."

Indeed, patient understanding is a key factor in getting healthcare professionals, governments and insurance companies to adopt and pay for PM, particularly when these targeted treatments are often more costly than traditional medical methods.

With PM, the same drug isn't given to millions of people. It's a targeted treatment regime. While that reduced patient pool means an increased cost, there can be long-term benefits. Increased efficiency and prevention may result in fewer drugs being prescribed. And PM may also result in the reduction of secondary costs as a result of overdosing, incorrect prescriptions and adverse drug reactions.

"If PM can be successfully integrated into the healthcare system at a reasonable cost, it represent a significant improvement in the treatment of chronic disease," says Katsanis.

But she warns that marketers need to proceed with caution: "The promotion of personalized medications will increasingly focus on the healthy patient with a genetic disposition for a particular illness. While this might lead to new and potentially greater opportunities for marketers, it might also result in the targeting of healthy patients who don't actually need treatment for an active disease. Ultimately, this could increase healthcare costs and cause unnecessary patient treatment."

Source: Concordia University

Read More

How does the brain react to virtual reality? Completely different pattern of activity in brain

Illusions (stock image). UCLA neurophysicists have found that space-mapping neurons in the brain react differently to virtual reality than they do to real-world environments. Credit: © agsandrew / Fotolia

UCLA neurophysicists have found that space-mapping neurons in the brain react differently to virtual reality than they do to real-world environments. Their findings could be significant for people who use virtual reality for gaming, military, commercial, scientific or other purposes.

"The pattern of activity in a brain region involved in spatial learning in the virtual world is completely different than when it processes activity in the real world," said Mayank Mehta, a UCLA professor of physics, neurology and neurobiology in the UCLA College and the study's senior author. "Since so many people are using virtual reality, it is important to understand why there are such big differences."

The study was published today in the journal Nature Neuroscience.

The scientists were studying the hippocampus, a region of the brain involved in diseases such as Alzheimer's, stroke, depression, schizophrenia, epilepsy and post-traumatic stress disorder. The hippocampus also plays an important role in forming new memories and creating mental maps of space. For example, when a person explores a room, hippocampal neurons become selectively active, providing a "cognitive map" of the environment.

The mechanisms by which the brain makes those cognitive maps remains a mystery, but neuroscientists have surmised that the hippocampus computes distances between the subject and surrounding landmarks, such as buildings and mountains. But in a real maze, other cues, such as smells and sounds, can also help the brain determine spaces and distances.

To test whether the hippocampus could actually form spatial maps using only visual landmarks, Mehta's team devised a noninvasive virtual reality environment and studied how the hippocampal neurons in the brains of rats reacted in the virtual world without the ability to use smells and sounds as cues.

Researchers placed a small harness around rats and put them on a treadmill surrounded by a "virtual world" on large video screens -- a virtual environment they describe as even more immersive than IMAX -- in an otherwise dark, quiet room. The scientists measured the rats' behavior and the activity of hundreds of neurons in their hippocampi, said UCLA graduate student Lavanya Acharya, a lead author on the research.

The researchers also measured the rats' behavior and neural activity when they walked in a real room designed to look exactly like the virtual reality room.

The scientists were surprised to find that the results from the virtual and real environments were entirely different. In the virtual world, the rats' hippocampal neurons seemed to fire completely randomly, as if the neurons had no idea where the rat was -- even though the rats seemed to behave perfectly normally in the real and virtual worlds.

"The 'map' disappeared completely," said Mehta, director of a W.M. Keck Foundation Neurophysics center and a member of UCLA's Brain Research Institute. "Nobody expected this. The neuron activity was a random function of the rat's position in the virtual world."

Explained Zahra Aghajan, a UCLA graduate student and another of the study's lead authors: 

"In fact, careful mathematical analysis showed that neurons in the virtual world were calculating the amount of distance the rat had walked, regardless of where he was in the virtual space."

They also were shocked to find that although the rats' hippocampal neurons were highly active in the real-world environment, more than half of those neurons shut down in the virtual space.

The virtual world used in the study was very similar to virtual reality environments used by humans, and neurons in a rat's brain would be very hard to distinguish from neurons in the human brain, Mehta said.

His conclusion: "The neural pattern in virtual reality is substantially different from the activity pattern in the real world. We need to fully understand how virtual reality affects the brain."

Neurons Bach would appreciate

In addition to analyzing the activity of individual neurons, Mehta's team studied larger groups of the brain cells. Previous research, including studies by his group, have revealed that groups of neurons create a complex pattern using brain rhythms.

"These complex rhythms are crucial for learning and memory, but we can't hear or feel these rhythms in our brain. They are hidden under the hood from us," Mehta said. "The complex pattern they make defies human imagination. The neurons in this memory-making region talk to each other using two entirely different languages at the same time. One of those languages is based on rhythm; the other is based on intensity."

Every neuron in the hippocampus speaks the two languages simultaneously, Mehta said, comparing the phenomenon to the multiple concurrent melodies of a Bach fugue.

Mehta's group reports that in the virtual world, the language based on rhythm has a similar structure to that in the real world, even though it says something entirely different in the two worlds. The language based on intensity, however, is entirely disrupted.

When people walk or try to remember something, the activity in the hippocampus becomes very rhythmic and these complex, rhythmic patterns appear, Mehta said. Those rhythms facilitate the formation of memories and our ability to recall them. Mehta hypothesizes that in some people with learning and memory disorders, these rhythms are impaired.

"Neurons involved in memory interact with other parts of the hippocampus like an orchestra," Mehta said. "It's not enough for every violinist and every trumpet player to play their music flawlessly. They also have to be perfectly synchronized."

Mehta believes that by retuning and synchronizing these rhythms, doctors will be able to repair damaged memory, but said doing so remains a huge challenge.

"The need to repair memories is enormous," noted Mehta, who said neurons and synapses -- the connections between neurons -- are amazingly complex machines.

Previous research by Mehta showed that the hippocampal circuit rapidly evolves with learning and that brain rhythms are crucial for this process. Mehta conducts his research with rats because analyzing complex brain circuits and neural activity with high precision currently is not possible in humans.

Other co-authors of the study were Jason Moore, a UCLA graduate student; Cliff Vuong, a research assistant who conducted the research as a UCLA undergraduate; and UCLA postdoctoral scholar Jesse Cushman. The research was funded by the W.M. Keck Foundation and the National Institutes of Health.

Source: University of California - Los Angeles

Read More

Lost memories might be able to be restored, suggests research into marine snail

New UCLA research indicates that lost memories can be restored. The findings offer some hope for patients in the early stages of Alzheimer's disease.

New UCLA research indicates that lost memories can be restored. The findings offer some hope for patients in the early stages of Alzheimer's disease.

For decades, most neuroscientists have believed that memories are stored at the synapses -- the connections between brain cells, or neurons -- which are destroyed by Alzheimer's disease. The new study provides evidence contradicting the idea that long-term memory is stored at synapses.

"Long-term memory is not stored at the synapse," said David Glanzman, a senior author of the study, and a UCLA professor of integrative biology and physiology and of neurobiology. 

"That's a radical idea, but that's where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won't be easy, but I believe it's possible."

The findings were published recently in eLife.

Glanzman's research team studies a type of marine snail called Aplysia to understand the animal's learning and memory. The Aplysia displays a defensive response to protect its gill from potential harm, and the researchers are especially interested in its withdrawal reflex and the sensory and motor neurons that produce it.

They enhanced the snail's withdrawal reflex by giving it several mild electrical shocks on its tail. The enhancement lasts for days after a series of electrical shocks, which indicates the snail's long-term memory. Glanzman explained that the shock causes the hormone serotonin to be released in the snail's central nervous system.

Long-term memory is a function of the growth of new synaptic connections caused by the serotonin, said Glanzman, a member of UCLA's Brain Research Institute. As long-term memories are formed, the brain creates new proteins that are involved in making new synapses. If that process is disrupted -- for example by a concussion or other injury -- the proteins may not be synthesized and long-term memories cannot form. (This is why people cannot remember what happened moments before a concussion.)

"If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn't remember the training," 

Glanzman said. "However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later. In other words, once memories are formed, if you temporarily disrupt protein synthesis, it doesn't affect long-term memory. That's true in the Aplysia and in human's brains." (This explains why people's older memories typically survive following a concussion.)

Glanzman's team found the same mechanism held true when studying the snail's neurons in a Petri dish. The researchers placed the sensory and motor neurons that mediate the snail's withdrawal reflex in a Petri dish, where the neurons re-formed the synaptic connections that existed when the neurons were inside the snail's body. When serotonin was added to the dish, new synaptic connections formed between the sensory and motor neurons. But if the addition of serotonin was immediately followed by the addition of a substance that inhibits protein synthesis, the new synaptic growth was blocked; long-term memory could not be formed.

The researchers also wanted to understand whether synapses disappeared when memories did. To find out, they counted the number of synapses in the dish and then, 24 hours later, added a protein synthesis inhibitor. One day later, they re-counted the synapses.

What they found was that new synapses had grown and the synaptic connections between the neurons had been strengthened; late treatment with the protein synthesis inhibitor did not disrupt the long-term memory. The phenomenon is extremely similar to what happens in the snail's nervous system during this type of simple learning, Glanzman said.

Next, the scientists added serotonin to a Petri dish containing a sensory neuron and motor neuron, waited 24 hours, and then added another brief pulse of serotonin -- which served to remind the neurons of the original training -- and immediately afterward add the protein synthesis inhibitor. This time, they found that synaptic growth and memory were erased. When they re-counted the synapses, they found that the number had reset to the number before the training, Glanzman said. This suggests that the "reminder" pulse of serotonin triggered a new round of memory consolidation, and that inhibiting protein synthesis during this "reconsolidation" erased the memory in the neurons.

If the prevailing wisdom were true -- that memories are stored in the synapses -- the researchers should have found that the lost synapses were the same ones that had grown in response to the serotonin. But that's not what happened: Instead, they found that some of the new synapses were still present and some were gone, and that some of the original ones were gone, too.

Glanzman said there was no obvious pattern to which synapses stayed and which disappeared, which implied that memory is not stored in synapses.

When the scientists repeated the experiment in the snail, and then gave the animal a modest number of tail shocks -- which do not produce long-term memory in a naive snail -- the memory they thought had been completely erased returned. This implies that synaptic connections that were lost were apparently restored.

"That suggests that the memory is not in the synapses but somewhere else," Glanzman said. 

"We think it's in the nucleus of the neurons. We haven't proved that, though."

Glanzman said the research could have significant implications for people with Alzheimer's disease. Specifically, just because the disease is known to destroy synapses in the brain doesn't mean that memories are destroyed.

"As long as the neurons are still alive, the memory will still be there, which means you may be able to recover some of the lost memories in the early stages of Alzheimer's," he said.

Glanzman added that in the later stages of the disease, neurons die, which likely means that the memories cannot be recovered.

The cellular and molecular processes seem to be very similar between the marine snail and humans, even though the snail has approximately 20,000 neurons and humans have about 1 trillion. Neurons each have several thousand synapses.

Glanzman used to believe that traumatic memories could be erased but he has changed his mind. He now believes that, because memories are stored in the nucleus, it may be much more difficult to modify them. He will continue to study how the marine snail's memories are restored and how synapses re-grow.

Co-authors of the study include Shanping Chen, Diancai Cai and Kaycey Pearce, research associates in Glanzman's laboratory.

The research was funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health and the National Science Foundation.

Almost all the processes that are involved in memory in the snail also have been shown to be involved in memory in the brains of mammals, Glanzman said.

In a 1997 study published in the journal Science, Glanzman and colleagues identified a cellular mechanism in the Aplysia that plays an important role in learning and memory. A protein called N-methyl D-aspartate, or NMDA, receptor enhances the strength of synaptic connections in the nervous system and plays a vital role in memory and in certain kinds of learning in the mammalian brain as well. Glanzman's demonstration that the NMDA receptor plays a critical role in learning in a simple animal like the marine snail was entirely unexpected at the time.

Source: University of California, Los Angeles

Read More

CASIS research set for launch aboard SpaceX mission to space station

The Bone Densitometer developed by Techshot, Inc. will enable X-ray testing for research studies aboard the International Space Station. Credit: CASIS

This fall marks another commercial cargo flight to the International Space Station. In September, SpaceX's Dragon spacecraft is scheduled to blast off to the orbital laboratory carrying supplies and investigations as part of the company's fourth contracted mission to the complex.

Included in the cargo will be the third suite of research investigations sponsored by the Center for the Advancement of Science in Space (CASIS). With the role of managing the U.S. National Laboratory on the space station, CASIS is responsible for brokering and facilitating research investigations on the station with clear Earth applications and benefits.

The latest collection of CASIS-sponsored research, termed Advancing Research Knowledge (ARK)-2, centers heavily on life sciences. Studies include those focused on drug development, disease understanding and validation testing. Each investigation will use the unique conditions aboard the space station to advance researchers' understanding in those areas of study.

Additionally, CASIS and NASA have partnered with Techshot Inc., of Greenville, Indiana, to develop a new hardware device capable of assisting with research that may improve understandings of muscle wasting and diseases like osteoporosis.

The CASIS-sponsored hardware and life science investigations destined for the space station's national laboratory include the Bone Densitometer, which will be the first X-ray machine installed on the space station. A joint project between CASIS, NASA and Techshot, the facility will be instrumental in conducting rodent research on station. The Bone 

Densitometer will allow astronauts to examine bone density of model organisms in space through the use of Dual-Energy X-ray Absorptiometry (DEXA) technology. In short, researchers will be able to assess bone density loss by measuring energy levels absorbed by bones via the device.

The Rodent Research-1 investigation kicks off a series of NASA and CASIS-sponsored investigations focused on rodent research aboard the space station. The study will be the first to use the Bone Densitometer in an effort to help scientists examine the effects of long duration spaceflight. There are numerous applications to these investigations including studying bone loss, muscle atrophy and cardiovascular anomalies. However, the primary focus of this inaugural mission will be to assess the operational capabilities of the new hardware designed for these investigations.

The Drug Metabolism study will assist researchers in the area of drug development and human biology. This investigation is led by a scientist from the U.S. Department of Veteran Affairs, Dr. Timothy Hammond, who is looking to study yeast cells in microgravity. The goal of this investigation is to explore the changes in these cells in space to improve drug development for various diseases, including cancer therapeutics.

The Protein Crystal Optimization study is an investigation aiming to leverage the unique location of the space station to examine the internal structure of three medically important proteins. The space environment should allow researchers to grow the selected protein crystals to an optimal size and quality to allow for closer examination via neutron diffraction. This protein crystal growth in microgravity may reveal new characteristics that are masked by gravity on Earth. By studying these three proteins, medically relevant to salmonella infection, peptic ulcer disease, and biomarkers for heart attack and liver disease, researchers can apply insights towards improved treatments.

A New Era In Commercial Use of the Space Station

The space station's national laboratory affords researchers the ability to conduct experiments in a distinctive environment with factors and variables that are near impossible to replicate on the ground. With access to our nation's only orbiting laboratory, CASIS works with new and non-traditional users to take advantage of this resource. A great example of novel commercial research heading to station is the Cobra Puma Golf investigation.

The Cobra Puma Golf-electroplating investigation, also launching aboard SpaceX, is a materials science investigation sponsored by CASIS in collaboration with COBRA PUMA Golf (CPG). The CPG research and development team will examine the impacts of microgravity on electroplating -- the process of coating a metallic surface using an electric current. The study will test a variety of coating substances on materials used in golf equipment manufacturing. The insight gained from this investigation will aid CPG in identifying improved material development techniques.

CPG's project is another example of a commercial user leveraging the capabilities of the ISS National Lab to advance ground research. Through brokering research investigations with commercial companies, CASIS hopes to demonstrate the space station is not only a test-bed for groundbreaking research and development, but a unique laboratory that can help differentiate investigations initiatives from ground-based studies.

The mission is another milestone for the space community, showcasing how commercial endeavors can work hand-in-hand with research goals. The studies of ARK-2 exemplify the diverse possibilities for the space station and users of the research platform. From commercial launch providers that transport investigations to space, to commercial researchers looking to use the national laboratory, science in space is good for life on Earth.

Source: NASA

Read More

Infectious prion protein discovered in urine of patients with variant Creutzfeldt-Jakob disease

Claudio Soto, Ph.D., in one of his labs at The University of Texas Health Science Center at Houston (UTHealth). Credit: Image courtesy of University of Texas Health Science Center at Houston

The misfolded and infectious prion protein that is a marker for variant Creutzfeldt-Jakob disease – linked to the consumption of infected cattle meat – has been detected in the urine of patients with the disease by researchers at The University of Texas Health Science Center at Houston (UTHealth) Medical School.

The results of the international study, led by Claudio Soto, Ph.D., professor of neurology at the UTHealth Medical School, will be published in the Aug. 7 issue of the New England Journal of Medicine.

Variant Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals – also known as Mad Cow disease – are fatal neurodegenerative disorders. There are currently no noninvasive tools available to diagnose the disease and there are no treatments.

Sporadic Creutzfeldt-Jakob disease occurs worldwide at a rate of around 1 new case per million people per year. The variant form is a new disease occurring in people who either ate the beef of cows with bovine spongiform encephalopathy or, in the case of three patients in the United Kingdom, received blood transfusions from asymptomatic infected donors.

The international team of researchers analyzed urine samples from 68 patients with sporadic Creutzfeldt-Jakob disease, 14 patients with variant Creutzfeldt-Jakob disease, four patients with genetic prion diseases, 50 patients with other neurodegenerative diseases, 50 patients with nondegenerative neurologic diseases and 52 healthy persons.

Soto’s laboratory used a protein misfolding cyclic amplification assay, invented in the lab, which mimics the prion replication process in vitro that occurs in prion disease. The misfolded prion proteins were detected in the urine of 13 of 14 patients with variant Creutzfeldt-Jakob disease. The single patient whose urine was negative had been receiving an experimental treatment of pentosan polysulfate directly into the brain. No misfolded prion proteins were detected in the urine of any the other study subjects, including the patients who had sporadic Creutzfeldt-Jakob disease.

“What could be less invasive than detecting this disease in urine? The fact that we were able to detect just the variant Creutzfeldt-Jakob disease form in the urine is very important. This could lead to the development of commercial technology for diagnosis as well as to determine the safety of donated blood and urinary products,” said Soto, who is the director of The George and Cynthia Mitchell Center for Research in Alzheimer’s disease and Related Brain Disorders, and founder of Amprion Inc, a biotech company developing the cyclic amplification technology for commercial application.

According to the World Health Organization (WHO), variant Creutzfeldt-Jakob disease affects younger patients, who have a median age of 28 at death, compared to sporadic Creutzfeldt-Jakob disease with a median age of 68. Most patients, after diagnosis of either form, live less than a year before death.

As of June 2, 2014, 177 of 229 people in the world with Creutzfeldt-Jakob disease were from the United Kingdom. A 2013 study published in the British Medical Journal has estimated that approximately 30,000 people in the United Kingdom might be carriers of the variant form of the disease.

“This study reports, for the first time, the detection of the abnormal prion protein in the urine from patients with variant Creutzfeldt-Jakob disease using the protein misfolding amplification technique pioneered by Dr. Claudio Soto,” said co-author James W. Ironside, FMedSci, FRSE, professor of clinical neuropathology at the National CJD Research and Surveillance Unit at the University of Edinburgh. “This has great potential to allow the development of a highly sensitive and specific non-invasive test that can be used for the diagnosis of variant Creutzfeldt-Jakob disease, and potentially as a screening tool for variant Creutzfeldt-Jakob disease infection in asymptomatic individuals, which is a topic of current interest in the United Kingdom.”

Source: University of Texas Health Science Center at Houston

Read More

What bank voles can teach us about prion disease transmission and neurodegeneration

This image shows accumulation of misfolded, toxic prion protein (brown staining) in the brain of a transgenic mouse expressing bank vole PrP and challenged with human variant Creutzfeldt-Jakob disease (vCJD) prions. Credit: Image courtesy of Dr. Joel Watts

When cannibals ate brains of people who died from prion disease, many of them fell ill with the fatal neurodegenerative disease as well. Likewise, when cows were fed protein contaminated with bovine prions, many of them developed mad cow disease. On the other hand, transmission of prions between species, for example from cows, sheep, or deer to humans, is -- fortunately -- inefficient, and only a small proportion of exposed recipients become sick within their lifetimes.

A study published on April 3rd in PLOS Pathogens takes a close look at one exception to this rule: bank voles appear to lack a species barrier for prion transmission, and their universal susceptibility turns out to be both informative and useful for the development of strategies to prevent prion transmission.
Prions are misfolded, toxic versions of a protein called PrP, which in its normal form is present in all mammalian species that have been examined. Toxic prions are "infectious"; they can induce existing, properly folded PrP proteins to convert into the disease-associated prion form. Prion diseases are rare, but they share features with more common neurodegenerative diseases like Alzheimer's disease.

Trying to understand the unusual susceptibility of bank voles to prions from other species, Stanley Prusiner, Joel Watts, Kurt Giles and colleagues, from the University of California in San Francisco, USA, first tested whether the susceptibility is an intrinsic property of the voles' PrP, or whether other factors present in these rodents make them vulnerable.

The scientists introduced into mice the gene that codes for the normal bank vole prion protein, thereby generating mice that express bank vole PrP, but not mouse PrP. When these mice get older, some of them spontaneously develop neurologic illness, but in the younger ones the bank vole PrP is in its normal, benign folded state. The scientists then exposed young mice to toxic misfolded prions from 8 different species, including human, cattle, elk, sheep, and hamster.

They found that all of these foreign-species prions can cause prion disease in the transgenic mice, and that the disease develops often more rapidly than it does in bank voles. The latter is likely because the transgenic mice express higher levels of bank vole PrP than are naturally present in the voles.

The results show that the universal susceptibility of bank voles to cross-species prion transmission is an intrinsic property of bank vole PrP. Because the transgenic mice develop prion disease rapidly, the scientists propose that the mice will be useful tools in studying the processes by which toxic prions "convert" healthy PrP and thereby destroy the brain. And because that process is similar across many neurodegenerative diseases, better understanding prion disease development might have broader implications.

Source:  PLOS

Read More

Scrapie could breach the species barrier

Scrapie is a neurodegenerative disease that has been known for centuries and which affects sheep and goats. Credit: INRA/Florent Giffard

INRA scientists have shown for the first time that the pathogens responsible for scrapie in small ruminants (prions) have the potential to convert the human prion protein from a healthy state to a pathological state. In mice models reproducing the human species barrier, this prion induces a disease similar to Creutzfeldt-Jakob disease. These primary results published in Nature Communications on 16 December 2014, stress the necessity to reassess the transmission of this disease to humans.

Scrapie is a neurodegenerative disease that has been known for centuries and which affects sheep and goats. Similar to Bovine Spongiform Encephalopathy (BSE) or mad cow disease, scrapie is caused by a transmissible pathogen protein called prion.

However, and contrary to BSE[1], epidemiological studies have never been able to establish a link between this disease and the occurrence of prion diseases in humans. "Risks of transmitting scrapie to humans (zoonose) were hitherto considered negligible because of the species barrier that naturally prevents prion propagation between species," said Olivier 

Andreoletti, INRA scientist who led the present study.

Researchers at INRA studied the permeability of the human transmission barrier to pathogens responsible for scrapie, using animal models specifically developed for this purpose. This approach previously allowed the confirmation of the zoonotic nature of prions responsible for BSE in cows and of the variant of Creutzfeldt-Jakob disease in humans (vCJD).

Unexpectedly, in these rodent models, certain pathogens responsible for scrapie were able to cross the transmission barrier. Moreover, the pathogens that propagated through this barrier were undistinguishable from the prions causing the sporadic form of Creutzfeldt-Jakob disease (sCJD). This data suggest a potential link between the occurrence of certain sCJD and these animal prions.

"Since CJD is scarce, about 1 case per million and per year, and incubation periods are usually long -several decades- it is extremely difficult for epidemiological studies to try and make this link," explains Olivier Andreoletti.

In their conclusions, the authors stress the fact that CJD cases are rare though scrapie has been circulating for centuries in small ruminants for which we eat the meat. Even if in future studies scrapie is finally confirmed to have a zoonotic potential, the authors consider that this disease does not constitute a new major risk for public health.

Source: INRA-France

Read More