Posts tagged nerve regeneration
Articles and news from the latest research reports.
(Image caption: The presence of p45 (green staining) and p75 (red staining) indicates that motor neurons increase both p45 and p75 expression after sciatic nerve injury in an animal. Image credit: Courtesy of the Salk Institute for Biological Studies)
Scientists uncover new clues to repairing an injured spinal cord
Frogs, dogs, whales, snails can all do it, but humans and primates can’t. Regrow nerves after an injury, that is—while many animals have this ability, humans don’t. But new research from the Salk Institute suggests that a small molecule may be able to convince damaged nerves to grow and effectively rewire circuits. Such a feat could eventually lead to therapies for the thousands of Americans with severe spinal cord injuries and paralysis.
"This research implies that we might be able to mimic neuronal repair processes that occur naturally in lower animals, which would be very exciting," says the study’s senior author and Salk professor Kuo-Fen Lee. The results were published today in PLOS Biology.
For a damaged nerve to regain function, its long, signal-transmitting extensions known as axons need to grow and establish new connections to other cells.
In a study published last summer in PLOS ONE, Lee and his colleagues found that the protein p45 promotes nerve regeneration by preventing the axon sheath (known as myelin) from inhibiting regrowth. However, humans, primates and some other more advanced vertebrates don’t have p45. Instead, the researchers discovered a different protein, p75, that binds to the axon’s myelin when nerve damage occurs in these animals. Instead of promoting nerve regeneration, p75 actually halts growth in damaged nerves.
"We don’t know why this nerve regeneration doesn’t occur in humans. We can speculate that the brain has so many neural connections that this regeneration is not absolutely necessary," Lee says.
In the study published today, the scientists looked at how two p75 proteins bind together and form a pair that latches onto the inhibitors released from damaged myelin.
By studying the configurations of the proteins in solutions using nuclear magnetic resonance (NMR) technology, the researchers found that the growth-promoting p45 could disrupt the p75 pairing.
"For reasons that are not understood, when p45 comes in, it breaks the pair apart," says Lee, holder of the Helen McLoraine Chair in Molecular Neurobiology.
What’s more, the p45 protein was able to bind to the specific region in the p75 protein that is critical for the formation of the p75 pair, thus decreasing the amount of p75 pairs that bond to inhibitors release from myelin. With less p75 pairs available to bond to inhibitor signals, axons were able to regrow.
The findings suggest that an agent—either p45 or another disrupting molecule—that can effectively break the p75 pair could offer a possible therapy for spinal cord damage.
One method of therapy could be to introduce more p45 protein to injured neurons, but a smarter tactic might be to introduce a small molecule that jams the link between the two p75 proteins, Lee says. “Such an agent could possibly get through the blood-brain barrier and to the site of spinal cord injuries,” he says.
The next step will be to see if introducing p45 helps regenerate damaged human nerves. “That is what we hope to do in the future,” Lee says.
(Image caption: Adult neurons are seen without (top) and following (below) treatment to inactivate Rb. Following treatment, the neurons show an increase in growth (branching) of axons. Credit: Bhagat Singh)
Scientists discover a new way to enhance nerve growth following injury
New research published today by researchers at the University of Calgary’s Hotchkiss Brain Institute uncovers a mechanism to promote growth in damaged nerve cells.
Dr. Doug Zochodne, a professor in the Department of Clinical Neurosciences, and his team have discovered a key molecule that directly regulates nerve cell growth in the damaged nervous system. This surprising discovery was published in the prestigious journal Nature Communications, with lead authors Kim Christie and Anand Krishnan.
“We have discovered that a protein called Retinoblastoma (Rb) is present in adult neurons,” explains Zochodne. “This protein appears to normally act as a brake – preventing nerve growth. What we have shown is that by inactivating Rb, we can release the brake and coax nerves to grow much faster.”
Clues from cancer
Zochodne and his team decided to look for Rb in nerve cells because of its known role in regulating cell growth elsewhere in the body.
“We know that cancer is characterized by excessive cell growth and we also know that Rb is often functioning abnormally in cancer,” says Zochodne. “So if cancer is able to release this brake and increase cell growth, we thought we’d try to mimic this same action in nerve cells and encourage growth where we want it.”
The key to this methodology, as Zochodne explains, is shutting down the brake for a very short, controlled period of time in order to avoid adverse effects such as excessive cell growth that could lead to cancer.
“In our tests, we were able to do this for a short amount of time,” says Zochodne. “We didn’t see any negative results, which leaves us optimistic that this could one day be used as a safe treatment for patients suffering from nerve damage.”
Peripheral nerve injuries and illnesses
So far, Zochodne is only investigating this technique in the peripheral nervous system. Peripheral nerves connect the brain and spinal cord to the body and without them, there is no movement or sensation. Peripheral nerve damage can be incredibly debilitating, with patients experiencing symptoms like pain, tingling, numbness or difficulty co-ordinating hands, feet, arms or legs.
As Zochodne explains, “peripheral nerve damage is surprisingly common. We see patients with cut or crushed nerves from motor vehicle accidents and we also see patients that suffer from conditions called neuropathies – a range of disorders that damage peripheral nerves.”
For example, diabetic neuropathy is more common than multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) combined. More than half of all diabetics have some form of nerve pain and currently there is no treatment to stop damage or reverse it.
Facility a one-stop shop for translating discoveries from the lab into the clinic
Developing safe and effective therapies for conditions such as peripheral nerve disorders requires the ability to take investigations from cells in a petri dish to patients in a clinic. Zochodne and his team have been able to do that thanks in part to a preclinical facility that opened at the Hotchkiss Brain Institute (HBI) in 2010. The Regeneration Unit in Neurobiology (RUN) was created through a partnership between the HBI, the University of Calgary and the Canada-Alberta Western Economic Partnership Agreement.
“The RUN facility has been critical for this research,” says Zochodne. “It provides the resources and cutting-edge equipment that we need all in one facility. RUN has allowed us to take this idea from nerve cells, to animal models and eventually will help us investigate whether it could be a feasible treatment in humans. It’s an incredible asset.”
Targeting an aspect of Down syndrome
University of Michigan researchers have determined how a gene that is known to be defective in Down syndrome is regulated and how its dysregulation may lead to neurological defects, providing insights into potential therapeutic approaches to an aspect of the syndrome.
Normally, nerve cells called neurons undergo an intense period of extending and branching of neuronal protrusions around the time of birth. During this period, the neurons produce the proteins of the gene called Down syndrome cell-adhesion molecule, or Dscam, at high levels. After this phase, the growth and the levels of protein taper off.
However, in the brains of patients with Down syndrome, epilepsy and several other neurological disorders, the amount of Dscam remains high. The impact of the elevated Dscam amount on how neurons develop is unknown.
Bing Ye, a faculty member at U-M’s Life Sciences Institute, found that in the fruit fly Drosophila, the amount of Dscam proteins in a neuron determines the size to which a neuron extends its protrusions before it forms connections with other nerve cells. An overproduction of Dscam proteins leads to abnormally large neuronal protrusions.
Ye also identified two molecular pathways that converge to regulate the abundance of Dscam. One, dual leucine zipper kinase (DLK), which is involved in nerve regeneration, promotes the synthesis of Dscam proteins. Another, fragile X mental retardation protein (FMRP), which causes fragile X syndrome when defective, represses Dscam protein synthesis. Because humans share these genes with Drosophila, the DLK-FMRP-Dscam relationship presents a possible target for therapeutic intervention, Ye said.
Many genes are involved in neurological disorders like Down syndrome, and how molecular defects cause the disease is complex.
"But because of the important roles of Dscam in the development of neurons, its related defect is very likely to be an aspect of Down syndrome and it may be an aspect of the syndrome that can be treated," said Ye, an assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.
Ye’s next step is to test the effects of overexpression of Dscam in mice to see how it changes the development of the nervous system and the behavior of the animal.
Down syndrome occurs in about one in 830 newborns; an estimated 250,000 people in the U.S. have the condition, according to the National Library of Medicine’s Genetics Home Reference.
Nerve regeneration research and therapy may get boost from new discovery
A new mechanism for guiding the growth of nerves that involves cell-death machinery has been found by scientists at the University of Nevada, Reno that may bring advances in neurological medicine and research. The team obtained the evidence in studies of fruit flies and reported their discovery in an article published in the prestigious science publication Cell Reports.
"Although the fly is a relatively simple organism, almost every gene identified in this species appears to be carrying out similar functions in humans," said Thomas Kidd, associate professor in the University’s biology department in whose lab the work was performed.
The Kidd lab is part of a $10 million Center for Biomedical Research Excellence Project in Cell Biology of Signaling at the University, which is funded by the National Institute of Health’s Institute of General Medical Sciences. The project is also funded by the National Science Foundation.
"Flies are useful because the neural mechanisms we are studying are similar to those in mammals," said Gunnar Newquist, lead author of the Cell Reports article and a post-doctoral neuroscience researcher in Kidd’s lab. "We’ve found something no one has seen before, that blocking the cell-death pathway can make nerves deprived of guidance cues figure out the right way to connect with other neurons. This was completely unexpected and novel, but really exciting because it changes the way we look at nerve growth.
"Neurons have a natural ability to die, if they fail to make the right connections they usually die. Neurons, like most other cell types, have the capacity to commit suicide and many do so during the formation of the nervous system."
The wiring of nervous systems is composed of axons, specialized extensions of neurons that transmit electrical impulses. During development axons navigate long distances to their targets by using signals in their environment. Netrin-B is one of those signals. Kidd, Newquist and colleagues have shown that Netrin-B also keeps neurons alive.
"Take away the Netrin-B and growth and cell death goes haywire," Newquist said.
This led them to the discovery that the cell-death machinery is active in growing nerves, and appears to be an integral part of the navigation mechanism.
"We use fruit fly genetics to study how these axons navigate these long distances correctly when developing," Kidd said. "Understanding the mechanisms they use to navigate is of great interest, not only for understanding how our brains form, but also as a starting point to devise ways to stimulate the re-growth of axons after injury, especially spinal cord injuries.
"Our work suggests that therapeutics designed to keep neurons alive after injury may be able to stimulate neurons to start re-growing or sprouting new connections."
"I am very pleased to see Tom’s and Gunnar’s hard work come to fruition," said Chris von Bartheld, director of the University’s cell-biology COBRE and a professor in the University of Nevada School of Medicine. "Linking axonal path finding and cell death signaling opens exciting new venues to better understand both topics. It also shows that our recently established center in cell biology is achieving its goals of producing top-level biomedical research."
(Source: unr.edu)
Making Axons Branch and Grow to Help Nerve Regeneration After Injury
One molecule makes nerve cells grow longer. Another one makes them grow branches. These new experimental manipulations have taken researchers a step closer to understanding how nerve cells are repaired at their farthest reaches after injury. The research was recently published in the Journal of Neuroscience.
“If you injure a peripheral nerve, it will spontaneously regenerate, but it goes very slowly. We’re trying to speed that up,” said Dr. Jeffery Twiss, a professor and head of the biology department at Drexel University in the College of Arts and Sciences, who was senior author of the paper.
But, Twiss said, scientists still have a lot to learn about how nerve cells repair themselves. He and his colleagues are especially interested in how nerve cells are repaired in their longest-reaching sections, their axons. Axons can be up to a meter long in adult human nerve cells, extending away from the cell body toward neighboring nerve cells, with which they exchange signals. Restoring length to damaged axons is essential to restoring nerve function, but coordinating these repairs at a great distance from the cell’s nucleus involves a mix of complex processes within each cell. To gain insight into these processes, they have focused research, including the present study, on repair proteins that are created locally near an injury site in a nerve’s axon.
A step towards repairing the central nervous system
Despite recent advances in understanding the mechanisms of nerve injury, tissue-engineering solutions for repairing damage in the central nervous system (CNS) remain elusive, owing to the crucial and complex role played by the neural stem cell (NSC) niche. This zone, in which stem cells are retained after embryonic development for the production of new cells, exerts a tight control over many crucial tasks such as growth promotion and the recreation of essential biochemical and physical cues for neural cell differentiation.
According to the first author of the paper, Zaida Álvarez, from the Group on Biomaterials for Regenerative Therapies of the Institute for Bioengineering of Catalonia (IBEC), “in order to develop tissue-engineering strategies to repair damage to the CNS, it is essential to design biomaterials that closely mimic the NSC niche and its physical and biochemical characteristics”.
In the study headed by Soledad Alcántara of the Department of Pathology and Experimental Therapeutics, the team tested types of polylactic acid (PLA) with different proportions of isomers L and D/L, a biodegradable material allowing neural cell adhesion and growth, as materials for nerve regeneration. They found that one type, PLA with a proportion of isomers of 70/30, maintained the important pools of neuronal and glial progenitor cells in vitro. PLA 70/30 was more amorphous, degraded faster and, crucially, released significant amounts of L-lactate, which is essential for the maintenance and differentiation of neural progenitor cells. “The aim of the research was to find a biomaterial able to sustain the population of neural stem cells and to generate new differentiated cells in order to start the development of an implant that allows brain regeneration,” explains Dr Alcántara.
“The mechanical and surface properties of PLA70/30, which we used here in the form of microthin films, make it a good substrate for neural cell adhesion, proliferation and differentiation,” adds Álvarez. “The physical properties of this material and the release of L-lactate when it degrades, which provides an alternative oxidative substrate for neural cells, act synergistically to modulate progenitor phenotypes”, concludes the researcher.
The results suggest that the introduction of 3D patterns mimicking the architecture of the embryonic NSC niches on PLA70/30-based scaffolds may be a good starting point for the design of brain-implantable devices. “These will be able to induce or activate existing neural progenitor cells to self-renew and produce new neurons, boosting the CNS regenerative response in situ,” states Álvarez.
Enabling the CNS to regenerate could open doors to promising new strategies to tackle accidental damage as well as numerous diseases like stroke and degenerative disorders such as Parkinson’s and Alzheimer’s diseases.
Discovery may help nerve regeneration in spinal injury
Scientists at the Universities of Liverpool and Glasgow have uncovered a possible new method of enhancing nerve repair in the treatment of spinal cord injuries.
It is known that scar tissue, which forms following spinal cord injury, creates an impenetrable barrier to nerve regeneration, leading to the irreversible paralysis associated with spinal injuries. Scientists at Liverpool and Glasgow have discovered that long-chain sugars, called heparan sulfates, play a significant role in the process of scar formation in cell models in the laboratory.
Research findings have the potential to contribute to new strategies for manipulating the scarring process induced in spinal cord injury and improving the effectiveness of cell transplantation therapies in patients with this type of injury.
Scarring occurs due to the activation, change in shape, and stiffness of cells, called astrocytes, which are the major nerve support cells in the spinal cord. One possible way to repair nerve damage is transplantation of support cells from peripheral nerves, called Schwann cells. The team, however, found that these cells secrete heparan sulfate sugars, which promote scarring reactions and could reduce the effectiveness of nerve repair.
Scientists showed that these sugars can over-activate protein growth factors that promote astrocyte scarring. Significantly, however, they found this over-activation could be inhibited by chemically modified heparins made in the laboratory. These compounds could prevent the scarring reaction of astrocyte cells, opening up new opportunities for treatment of damaged nerve cells.
Professor Jerry Turnbull, from the University of Liverpool’s Institute of Integrative Biology, said: “Spinal injury is a devastating condition and can result in paralysis for life. The sugars we are investigating are produced by nearly every cell in the body, and are similar to the blood thinning drug heparin.
"We found that some sugar types promote scarring reaction, but remarkably other types, which can be chemically produced in the laboratory by modifying heparin, can prevent this in our cell models.
"Studies in animal cells are now needed, but the exciting thing about this work is that it could, in the future, provide a way of developing treatments for improving nerve repair in patients, using the body’s own Schwann cells, supplemented with specific sugars."
Professor Sue Barnett, from the University of Glasgow’s Institute of Infection, Immunity and Inflammation, said: “We had already shown that Schwann cells, identified as having the potential to promote nerve regrowth, induced scarring in spinal cord injury. Now that we know that they secrete these complex sugars, which lead to scarring, we have the opportunity to intervene in this process, and promote central nervous system repair.”
(Source: eurekalert.org)
Researchers identify gene required for nerve regeneration
A gene that is associated with regeneration of injured nerve cells has been identified by scientists at Penn State and Duke University. The team, led by Melissa Rolls, an assistant professor of biochemistry and molecular biology at Penn State, has found that a mutation in a single gene can entirely shut down the process by which axons — the parts of the nerve cell that are responsible for sending signals to other cells — regrow themselves after being cut or damaged. “We are hopeful that this discovery will open the door to new research related to spinal-cord and other neurological disorders in humans,” Rolls said. The journal Cell Reports published an early online copy of the paper (Nov. 1), and also will include the paper in the monthly issue of the journal, which will be published Nov. 29.
Study sheds light on role of exercise and androgens such as testosterone on nerve damage repair
A study by researchers from Emory University and Indiana University found that the beneficial effects daily exercise can have on the regeneration of nerves also require androgens such as testosterone in both males and females. It is the first report of both androgen-dependence of exercise on nerve regeneration and of an androgenic effect of exercise in females.
"The findings will provide a basis for the development of future treatment strategies for patients suffering peripheral nerve injuries," said Dale Sengelaub, professor in the Department of Psychological and Brain Sciences at IU. "And they underscore the need to tailor those treatments differently for men and women."
The researchers discussed the study on Monday at the Neuroscience 2012 scientific meeting in New Orleans.
Injuries to peripheral nerves are common. Hundreds of thousands of Americans are victims of traumatic injuries each year, and non-traumatic injuries, such as carpal tunnel syndrome, are found in even higher numbers. The researchers previously showed that two weeks of moderate daily exercise substantially improves regeneration of cut nerves and leads to functional recovery in mice, though different types of exercise are required to produce the effect in males and females. They now report that these beneficial effects of exercise require androgens such as testosterone in both males and females.
In the study they conducted, they exercised three groups of male and female mice. Nerves of the three groups were cut and surgically repaired. Once group received the drug flutamide, which blocks the androgen receptor. A second group received a placebo treatment. The third group was unexercised. Regenerating nerve fibers in the placebo group grew to more than twice the length of those in unexercised mice in both males and females. In flutamide-treated mice, the effects of exercise were blocked completely in both sexes.
The Society of Neuroscience is promoting the study (“Enhancement of peripheral axon regeneration by exercise requires androgen receptor signaling in both male and female mice”) to media covering the conference as a “Hot Topic.”
(Source: eurekalert.org)
Study Suggests Immune System Can Boost Nerve Regrowth
Modulating immune response to injury could accelerate the regeneration of severed peripheral nerves, a new study in an animal model has found. By altering activity of the macrophage cells that respond to injuries, researchers dramatically increased the rate at which nerve processes regrew.
Influencing the macrophages immediately after injury may affect the whole cascade of biochemical events that occurs after nerve damage, potentially eliminating the need to directly stimulate the growth of axons using nerve growth factors. If the results of this first-ever study can be applied to humans, they could one day lead to a new strategy for treating peripheral nerve injuries that typically result from trauma, surgical resection of tumors or radical prostectomy.
“Both scar formation and healing are the end results of two different cascades of biological processes that result from injuries,” said Ravi Bellamkonda, Carol Ann and David D. Flanagan professor in the Wallace H. Coulter Department of Biomedical Engineering and member of the Regenerative Engineering and Medicine Center at Georgia Tech and Emory University. “In this study, we show that by manipulating the immune system soon after injury, we can bias the system toward healing, and stimulate the natural repair mechanisms of the body.”
Beyond nerves, researchers believe their technique could also be applied to help regenerate other tissue – such as bone. The research was supported by the National Institutes of Health (NIH), and reported online Sept. 26, 2012, by the journal Biomaterials.