Biomechanism: Shuttle service in cells

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RUB research scientists find new components for protein transport.

(“Biomechanism.com“) — Research scientists at the Ruhr University Bochum discovered a new enzyme, which gives decisive insights into protein import into specific cellular organelles (peroxisomes). In the Journal of Biological Chemistry, the team of Prof. Erdmann (Medical Faculty, Department of Systemic Biochemistry) reports that the enzyme Ubp15p collaborates with two other proteins to convert the protein transport machinery back into its initial condition after work has been completed.

High magnification transmission electron microscope image of a human leukocyte, showing golgi, which is a structure involved in protein transport in the cytoplasm of the cell. Photo: Louisa Howard

The enzyme detaches a specific signal sequence from a protein which is important for transportation and recycling of this protein. A new sequence of protein can then commence. “With Ubp15p we could unravel a further mystery concerning the transport of proteins into peroxisomes”, explains Prof. Erdmann. “The comprehension of these organelles at a molecular level is a decisive prerequisite for the development of new diagnostic and therapeutic approaches for patients with peroxisomal disorders who only seldom survive the first year of their life.”

Shuttling to the peroxisome

Peroxisomes are multifunctional “tools.” They are involved, for example, in the catabolism of fatty acids, and detoxify poisonous hydrogen peroxide. A malfunction of these organelles, as is the case in Zellweger Syndrome disorders, can have disastrous influences on the functioning of the liver, kidneys and brain. To be able to function correctly, peroxisomes need specific proteins, but they cannot produce these themselves. Thus, a shuttle system consisting of several receptors has to import them from the cytosol. The receptors recognize the proteins specified for the peroxisomes within the cytosol and escort them to their destination. Here they bond with the membrane of the peroxisome and form part of the “gate” through which the proteins are transported into the interior. An export signal (ubiquitin) is attached to the receptors, which ensures that they are released from the peroxisome membrane and available for transport yet again. What subsequently happens to the ubiquitin signal remains to be clarified.

New export components discovered

In an earlier publication in Nature Cell Biology, Prof. Erdmann’s team had already described two motor proteins that withdraw the ubiquitin-marked receptor Pex5p from the membrane and transport it back into the cytosol. In a further paper (Nature Reviews Molecular Cell Biology), they postulated that this export of the receptor is mechanistically linked to the import of the peroxisomal protein. To date, it has however not been possible to detect the ubiquitin together with Pex5p in the cytosol. “We thus assumed that the ubiquitin is removed from the receptor during or shortly after export”, states Prof. Erdmann. His team, funded by the collaborative research center 642 of the German National Science Foundation (Sonderforschungsbereich 642 der Deutschen Forschungsgemeinschaft), has now established that the enzyme Ubp15p disconnects the export signal and collaborates with the two motor proteins to remove the receptor from the membrane of the peroxisome.

Enzyme could be important for recycling

The scientists managed to locate Ubp15p in living yeast cells and to prove that the enzyme comes into direct contact with one of the motor proteins to reach the peroxisomes. When Prof. Erdmann’s team deactivated the Ubp15p in the cells, the amount of ubiquitinated Pex5p increased. This result confirms the role of Ubp15p in cleaving the ubiquitin signal. The enzyme seems to have an important function in the import of proteins into the peroxisomes, particularly under stress conditions. “Ubp15p appears to play a vital role in the recycling of the receptor”, points out Prof. Erdmann.

Pregnancy hormone has unprecedented, powerful effect on spinal muscular atrophy

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‘Biggest increase anyone has seen’ in the production of essential compound for deadly childhood disease.

Researchers in Ottawa report new hope for the treatment of infants born with serious genetic disorder.

Over 1000 children in Canada are affected with Spinal Muscular Atrophy (SMA), a genetic disorder that causes muscle weakness and loss of motor control. In its most severe form survival of children with SMA beyond 5 years is rare. Although the disorder is caused by the loss of a specific gene, all infants and children with SMA have an untouched highly similar gene within their genetic make up. Activation of this copy gene has the potential to treat SMA, and thus has been a goal of researchers around the world. Now, researchers at the Children’s Hospital of Eastern Ontario Research Institute in Ottawa report the strongest such activation yet observed with attendant benefit on mice genetically engineered to have SMA.

When a woman gets pregnant, one of the ways to check for pregnancy is by doing a blood test. In this test, the amount of pregnancy hormone known as human chorionic gonadotropin (hCG) present in the blood is measured. This hormone is produced by the placenta and can be detected in the blood as well as the urine ten days after the ovum is fertilized by the sperm. -Biomechanism.com

PhD student Faraz Farooq working in the laboratory of University of Ottawa professor, Alex MacKenzie has discovered that the pregnancy hormone Prolactin, a Canadian discovery in itself, not only activates the copy gene but if given over time extends the lifespan of SMA mice by up to 60%. The research report is published today in the Journal of Clinical Investigation.

“Prolactin causes a dramatic regulation of copy gene SMN2 which results in high production of SMN protein, resulting in the extension in the lifespan of mice with SMA,” said Mr. Faraz Farooq. “Labs around the world have been trying to produce more protein from copy gene SMN2 but with Prolactin (an insulin like protein) we’re seeing up-regulation that’s more than tenfold. It’s the biggest increase anyone has yet seen in the SMA Field with any potential therapeutic compound. This represents a significant advance in search for a therapy for this disease.”

The laboratory testing of Prolactin on SMA not only shows an extended lifespan but also improved motor control. Prolactin has been used in clinical trials for unrelated studies, so it is expected that the path between pre-clinical validation and actual clinic trials of Prolactin with SMA patients will be reasonably short.

“News of prolactin’s role and effectiveness in SMN regulation breathes fresh hope into all of the SMA community,” said Martha Slay, president and co-founder of FightSMA. “FightSMA congratulates Dr. MacKenzie and his colleagues on this exciting breakthrough in SMA research.”

“We believe we’re moving in the direction of an effective pre-symptomatic treatment of kids with SMA,” said Dr. Alex MacKenzie, principal investigator, CHEO Research Institute. “We want to somehow stop the progress of this disorder in its tracks, and let our tiniest patients build strength. Today’s findings are not curative, but we think this is a breakthrough discovery. Hopefully by using different approaches to increase SMN protein we can develop a combination therapy for the treatment of SMA.”

Exercise has numerous beneficial effects on brain health and cognition, review suggests

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(“Biomechanism.com“) — It’s no secret that exercise has numerous beneficial effects on the body. However, a bevy of recent research suggests that these positive effects also extend to the brain, influencing cognition.

The reviewed studies suggest that both aerobic exercise and strength training can have significant positive effects on brain health and function, but more research is needed to better elucidate these effects. -Biomechanism.com

In a new review article highlighting the results of more than a hundred recent human and animal studies on this topic, Michelle W. Voss, of the University of Illinois at Urbana-Champaign, and her colleagues show that both aerobic exercise and strength training play a vital role in maintaining brain and cognitive health throughout life.

However, they also suggest that many unanswered questions remain in the field of exercise neuroscience—including how various aspects of exercise influence brain physiology and function and how human and animal studies relate to each other—and issue the call for further research to fill in these gaps.

The article, “Exercise, Brain and Cognition Across the Lifespan,” is published in the online edition of the  Journal of Applied Physiology.

Methodology

Using the findings from 111 recent studies, the researchers write a brief review showcasing the effects of aerobic exercise and strength training on humans ranging in age from children to elderly adults. They relate these findings to those in lab animals, such as rats and mice, which provide a window on the pathways through which exercise may enhance brain function.

Results

The review suggests that aerobic exercise is important for getting a head start during childhood on cognitive abilities that are important throughout life. For example, physical inactivity is associated with poorer academic performance and results on standard neuropsychological tests, while exercise programs appear to improve memory, attention, and decision-making. These effects also extend to young and elderly adults, with solid evidence for aerobic training benefiting executive functions, including multi-tasking, planning, and inhibition, and increasing the volume of brain structures important for memory. Although few studies have evaluated the effects of strength training on brain health in children, studies in older adults suggest that high-intensity and high-load training can improve memory.

Animal studies, primarily models that test the influence of aerobic exercise, suggest a variety of mechanisms responsible for these effects. For example, exercise appears to change brain structure, prompting the growth of new nerve cells and blood vessels. It also increases the production of neurochemicals, such as BDNF and IGF-1, that promote growth, differentiation, survival, and repair of brain cells.

Though this collection of studies clearly reveals the beneficial effects of exercise on the brain, it also highlights gaps in the scientific literature. For example, the review authors note that more research is needed on how exercise type might promote different effects on brain health and cognition. Similarly, they say, future research that integrates human and animal work will be necessary, such as studies that incorporate exercise over animals’ life spans to understand the effects of exercise at different time points, or human studies that include measures of BDNF, IGF-1, or other neurobiological markers.

Importance of the Findings

The reviewed studies suggest that both aerobic exercise and strength training can have significant positive effects on brain health and function, but more research is needed to better elucidate these effects.

“It is increasingly prevalent in the print media, television, and the Internet to be bombarded with advertisements for products and programs to enhance mental and physical health in a relatively painless fashion through miracle elixirs, computer-based training, or gaming programs, or brief exercise programs,” the authors say. “Although there is little convincing scientific evidence for such claims, there have been some promising developments in the scientific literature with regard to physical activity and exercise effects on cognitive and brain health.”

Study Team

In addition to Dr. Voss, the study team was comprised of Arthur F. Kramer, also of the University of Illinois at Urbana-Champaign, and Lindsay S. Nagamatsu and Teresa Liu-Ambrose, both of the University of British Columbia, Vancouver, BC.

Retinal cells thoughts to be the same are not, JHU biologist says

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The old adage “Looks can be deceiving” certainly rings true when it comes to people. But it is also accurate when describing special light-sensing cells in the eye, according to a Johns Hopkins University biologist.

Caption: This is associate professor Samer Hattar, a biologist at the Johns Hopkins University. Credit: Will Kirk/JHU

In a study recently published in Nature, a team led by Samer Hattar of the Department of Biology at the Krieger School of Arts and Sciences and Tudor Badea at the National Eye Institute found that these cells, which were thought to be identical and responsible for both setting the body’s circadian rhythm and the pupil’s reaction to light and darkness, are actually two different cells, each responsible for one of those tasks.

“In biology, as in life, you can’t always trust what you see,” said Hattar. “You have to delve deep to find out what’s really going on. This study has shown that two structurally similar neurons are actually quite different and distinct, communicate with different regions of the brain and influence different visual functions.”

The findings are significant, Hattar said, because doctors sometimes use pupillary light reflex (the pupil’s response to light and darkness) as a way of diagnosing patients who may have sleep problems, and those clinicians now must recognize that the cells controlling pupillary response and those controlling the sleep-wake cycle are different.

“Although the diagnosis may still be valid most of the time, it is important to remember that disrupted pupillary light response with normal sleep wake cycles or the opposite is possible, and caution should be exercised if clinicians only use pupillary light reflex for diagnosis purposes for deficits in non-image forming visual functions,” explained Shih-Kuo (Alen) Chen, a post-doctoral fellow in the Department of Biology and co-author of the Nature article.

Hattar’s research focuses on these special light-sensitive cells and how they regulate the physiology and behavior of mammals.

“In human beings, light has an impact on many of our physiological functions, including sleep and mood,” he explains. “We are interested in the cellular, molecular and behavioral pathways by which light has an impact on us, independent of how and what we literally ‘see’ with our eyes. This includes setting our internal, biological clock to the day and night and constricting our pupils to control the amount of light coming through to our retinas.”

In a previous study, Hattar’s team revealed that these cells — called “intrinsically photosensitive Retinal Ganglion Cells” — also play a role in image formation. Formerly, it was thought that the ipRGCs’ role was limited to sleep-wake cycles and pupillary responses.

Global bioterrorism threat analyzed for world animal health office

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(“Bio News“) — Around the globe, many nations are realizing that the potential for bioterrorism isn’t just about the U.S., officials say.

And because an intentional introduction of bacteria, a virus or a toxin could happen anywhere, the World Organization for Animal Health is issuing a paper aimed at prevention.

Around the globe, many nations are realizing that the potential for bioterrorism isn’t just about the U.S., officials say.

“Any emerging country that is beginning to think about maintaining international trade needs to be aware of the potential for bioterrorism,” said Dr. Neville Clarke, special assistant to the Texas A&M University System’s vice chancellor of agriculture.

Clarke is lead author of “Bioterrorism: intentional introduction of animal disease,” which appears in the animal health organization’s journal Scientific and Technical Review this month.

First off, bioterrorism is not new.

The intentional introduction of animal disease dates to the Middle Ages when “diseased carcasses and bodies were catapulted over enemy walls in attempts to induce sickness in humans or animals,” Clarke wrote with co-author Jennifer L. Rinderknecht, Texas AgriLife Research assistant.

Throughout time, similar practices ensued until 1975, when more than 160 countries at the Biological and Toxic Weapons Convention agreed to prohibit biological warfare programs, the article noted.

But, the authors say, evidence around the world indicates that the “development of biological agents continues in some countries.”

Clarke said that those farthest away from being prepared are the developing nations such as in Sub-Saharan Africa and Indonesia. He said the article would be helpful for nations that are wanting to protect their markets as they grow globally.

The article discusses potential perpetrators and their methods, priority diseases, modern biology, trade and regulatory restraints as listed by the World Organization for Animal Health, which is headquartered in Paris and known as OIE for Office International des Epizooties.

Clarke pointed to the live animal and fresh meat restrictions on imports from Brazil that are in place because there are still pockets of Foot-and-Mouth Disease in that South American country.

“That impairs their ability to export to the U.S.,” he said. “Trade restriction is one of the most important underlying issues that face countries. That makes bioterrorism everyone’s business.”

While the article deals specifically with intentional introductions, Clarke said the “clean up and control is same” for either type event.

“The only difference is in attribution,” he said. “If an act is intentional, then the focus goes to finding out who did it.”