Posts tagged myelin

Genetically engineered immune cells seem to promote healing in mice infected with a neurological disease similar to multiple sclerosis (MS), cleaning up lesions and allowing the mice to regain use of their legs and tails.

The new finding, by a team of University of Wisconsin School of Medicine and Public Health researchers, suggests that immune cells could be engineered to create a new type of treatment for people with MS. Currently, there are few good medications for MS, an autoimmune inflammatory disease that affects some 400,000 people in the United States, and none that reverse progress of the disease.

Dr. Michael Carrithers, assistant professor of neurology, led a team that created a specially designed macrophage – an immune cell whose name means “big eater.” Macrophages rush to the site of an injury or infection, to destroy bacteria and viruses and clear away damaged tissue. The research team added a human gene to the mouse immune cell, creating a macrophage that expressed a sodium channel called NaVI.5, which seems to enhance the cell’s immune response.

But because macrophages can also be part of the autoimmune response that damages the protective covering (myelin) of the nerves in people with MS, scientists weren’t sure whether the NaV1.5 macrophages would help or make the disease worse.

When the mice developed experimental autoimmune encephalomyelitis – the mouse version of MS — they found that the NaV1.5 macrophages sought out the lesions caused by the disease and promoted recovery.

“This finding was unexpected because we weren’t sure how much damage they would do, versus how much cleaning up they would do,” Carrithers says. “Some people thought the mice would get more ill, but we found that it protected them and they either had no disease or a very mild case.”

In follow-up experiments, regular mice that do not express the human gene were treated with the NaV1.5 macrophages after the onset of symptoms, which include weakness of the back and front limbs. The majority of these mice developed complete paralysis of their hindlimbs. Almost all of the mice that were treated with the Na1.5 macrophages regained the ability to walk. Mice treated with placebo solution or regular mouse macrophages that did not have NaV1.5 did not show any recovery or became more ill. In treated mice, the research team also found the NaV1.5 macrophages at the site of the lesions, and found smaller lesions and less damaged tissue in the treated mice.

Because the NaV1.5 variation is present in human immune cells, Carrithers says, “The questions are, ‘Why are these repair mechanisms deficient in patients with MS and what can we do to enhance them?’’’ He says the long-range goal is to develop the NaV1.5 enhanced macrophages as a treatment for people with MS.

The study is being published in the June issue of the Journal of Neuropathology and Experimental Neurology.

(Source: med.wisc.edu)

Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.

The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.

The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.

The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals’ MS symptoms improved.

“Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells,” said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.

“Our discovery of etifoxine’s effects on an MS animal model suggests that mitochondrial TSPO represents a potential therapeutic target for MS drug development,” said Deng.

“Drugs designed to more precisely bind to mitochondrial TSPO may help repair the myelin sheath of MS patients and thereby even help restore the transmission of signals in the central nervous system that enable normal motor, sensory and cognitive functions,” he said.

Deng added that better treatments for MS and other demyelinating diseases are needed, especially since current FDA-approved therapies do not repair the damage of immune attacks on the myelin sheath. 

The UC Davis research team hopes to further investigate the therapeutic applications of mitochondrial TSPO in drug development for MS and other autoimmune diseases. To identify more efficacious and safer drug candidates, they plan to pursue research grants that will enable them to test a variety of pharmacological compounds that bind to mitochondrial TSPO and other molecular targets in experimental models of MS and other myelin diseases.

(Source: ucdmc.ucdavis.edu)

By monitoring the behavior of a class of cells in the brains of living mice, neuroscientists at Johns Hopkins discovered that these cells remain highly dynamic in the adult brain, where they transform into cells that insulate nerve fibers and help form scars that aid in tissue repair.

Published online April 28 in the journal Nature Neuroscience, their work sheds light on how these multipurpose cells communicate with each other to maintain a highly regular, grid-like distribution throughout the brain and spinal cord. The disappearance of one of these so-called progenitor cells causes a neighbor to quickly divide to form a replacement, ensuring that cell loss and cell addition are kept in balance.

“There is a widely held misconception that the adult nervous system is static or fixed, and has a limited capacity for repair and regeneration,” says Dwight Bergles, Ph.D., professor of neuroscience and otolaryngology at the Johns Hopkins University School of Medicine. “But we found that these progenitor cells, called oligodendrocyte precursor cells (OPCs), are remarkably dynamic. Unlike most other adult brain cells, they are able to respond to the repair needs around them while maintaining their numbers.”

OPCs can mature to become oligodendrocytes — support cells in the brain and spinal cord responsible for wrapping nerve fibers to create insulation known as myelin. Without myelin, the electrical signals sent by neurons travel poorly and some cells die due to the lack of metabolic support from oligodendrocytes. It is the death of oligodendrocytes and the subsequent loss of myelin that leads to neurological disability in diseases such as multiple sclerosis.

During brain development, OPCs spread throughout the central nervous system and make large numbers of oligodendrocytes. Scientists know that few new oligodendrocytes are born in the healthy adult brain, yet the brain is flush with OPCs. However, the function of OPCs in the adult brain wasn’t clear.

To find out, Bergles and his team genetically modified mice so that their OPCs contained a fluorescent protein along their edges, giving crisp definition to their many fine branches that extend in every direction. Using special microscopes that allow imaging deep inside the brain, the team watched the activity of individual cells in living mice for over a month.

The researchers discovered that, far from being static, the OPCs were continuously moving through the brain tissue, extending their “tentacles” and repositioning themselves. Even though these progenitors are dynamic, each cell maintains its own area by repelling other OPCs when they come in contact.

“The cells seem to sense each other’s presence and know how to control the number of cells in their population,” says Bergles. “It looks like this process goes wrong in multiple sclerosis lesions, where there are reduced numbers of OPCs, a loss that may impair the cells’ ability to sense whether demyelination has occurred. We don’t yet know what molecules are involved in this process, but it’s something we’re actively working on.”

To see if OPCs do more than form new oligodendrocytes in the adult brain, the team tested their response to injury by using a laser to create a small wound in the brain. Surprisingly, OPCs migrated to the injury site and contributed to scar formation, a previously unsuspected role. The empty space in the OPC grid, created by the loss of the scar-forming OPCs, was then filled by cell division of neighboring OPCs, providing an explanation for why brain injury is often accompanied by proliferation of these cells.

“Scar cells are not oligodendrocytes, so the term ‘oligodendrocyte precursor cell’ may now be outdated,” says Bergles. “These cells are likely to have a broader role in tissue regeneration and repair than we thought. Because traumatic brain injuries, multiple sclerosis and other neurodegenerative diseases require tissue regeneration, we are eager to learn more about the functions of these enigmatic cells.”

Neuroscientists at UB’s Hunter James Kelly Research Institute show how turning down synthesis of a protein improves nerve, muscle function in common neuropathy.

A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo’s Hunter James Kelly Research Institute and their colleagues in Italy and England.

The institute is the research arm of the Hunter’s Hope Foundation, established in 1997 by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their infant son Hunter was diagnosed with Krabbe Leukodystrophy, an inherited fatal disorder of the nervous system. Hunter died in 2005 at the age of eight. The institute conducts research on myelin and its related diseases with the goal of developing new ways of understanding and treating conditions such as Krabbe disease and other leukodystrophies.

Charcot-Marie-Tooth or CMT disease, which affects the peripheral nerves, is among the most common of hereditary neurological disorders; it is a disease of myelin and it results from misfolded proteins in cells that produce myelin.

The new findings were published online earlier this month in The Journal of Experimental Medicine.

They may have relevance for other diseases that result from misfolded proteins, including Alzheimer’s disease, Parkinson’s, multiple sclerosis, Type 1 diabetes, cancer and mad cow disease.

The paper shows that missteps in translational homeostasis, the process of regulating new protein production so that cells maintain a precise balance between lipids and proteins, may be how some genetic mutations in CMT cause neuropathy.

CMT neuropathies are common, hereditary and progressive; in severe cases, patients end up in wheelchairs. These diseases significantly affect quality of life but not longevity, taking a major toll on patients, families and society, the researchers note.

“It’s possible that our finding could lead to the development of an effective treatment not just for CMT neuropathies but also for other diseases related to misfolded proteins,” says Lawrence Wrabetz, MD, director of the institute and professor of neurology and biochemistry in UB’s School of Medicine and Biomedical Sciences and senior author on the paper. Maurizio D’Antonio, of the Division of Genetics and Cell Biology of the San Raffaele Scientific Institute in Milan is first author; Wrabetz did most of this research while he was at San Raffaele, prior to coming to UB.

The research finding centers around the synthesis of misfolded proteins in Schwann cells, which make myelin in nerves. Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Many CMT neuropathies are associated with mutations in a gene known as P0, which glues the wraps of myelin together. Wrabetz has previously shown in experiments with transgenic mice that those mutations cause the myelin to break down, which in turn, causes degeneration of peripheral nerves and wasting of muscles.

When cells recognize that the misfolded proteins are being synthesized, cells respond by severely reducing protein production in an effort to correct the problem, Wrabetz explains. The cells commence protein synthesis again when a protein called Gadd34 gets involved.

“After cells have reacted to, and corrected, misfolding of proteins, the job of Gadd34 is to turn protein synthesis back on,” says Wrabetz. “What we have shown is that once Gadd34 is turned back on, it activates synthesis of proteins at a level that’s too high—that’s what causes more problems in myelination.

“We have provided proof of principle that Gadd34 causes a problem with translational homeostasis and that’s what causes some neuropathies,” says Wrabetz. “We’ve shown that if we just reduce Gadd34, we actually get better myelination. So, leaving protein synthesis turned partially off is better than turning it back on, completely.”

In both cultures and a transgenic mouse model of CMT neuropathies, the researchers improved myelin by reducing Gadd34 with salubrinal, a small molecule research drug. While salubrinal is not appropriate for human use, Wrabetz and colleagues at UB and elsewhere are working to develop derivatives that are appropriate.

“If we can demonstrate that a new version of this molecule is safe and effective, then it could be part of a new therapeutic strategy for CMT and possibly other misfolded protein diseases as well,” says Wrabetz.

And while CMT is the focus of this particular research, the work is helping scientists at the Hunter James Kelly Research Institute enrich their understanding of myelin disorders in general.

“What we learn in one disease, such as CMT, may inform how we think about toxins for others, such as Krabbe’s,” Wrabetz says. “We’d like to build a foundation and answer basic questions about where and when toxicity in diseases begin.”

The misfolded protein diseases are an interesting and challenging group of diseases to study, he continues. “CMT, for example, is caused by mutations in more than 40 different genes,” he says. “When there are so many different genes involved and so many different mechanisms, you have to find a unifying mechanism: this problem of Gadd34 turning protein synthesis on at too high a level could be one unifying mechanism. The hope is that this proof of principle applies to more than just CMT and may lead to improved treatments for Alzheimer’s, Parkinson’s, Type 1 diabetes and the other diseases caused by misfolded proteins.”

(Source: buffalo.edu)

A study out today in the journal Cell Stem Cell shows that human brain cells created by reprogramming skin cells are highly effective in treating myelin disorders, a family of diseases that includes multiple sclerosis and rare childhood disorders called pediatric leukodystrophies.

The study is the first successful attempt to employ human induced pluripotent stem cells (hiPSC) to produce a population of cells that are critical to neural signaling in the brain. In this instance, the researchers utilized cells crafted from human skin and transplanted them into animal models of myelin disease.

"This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., lead author of the study. "In fact, it appears that cells derived from this source are at least as effective as those created using embryonic or tissue-specific stem cells."

The discovery opens the door to potential new treatments using hiPSC-derived cells for a range of neurological diseases characterized by the loss of a specific cell population in the central nervous system called myelin. Like the insulation found on electrical wires, myelin is a fatty tissue that ensheathes the connections between nerve cells and ensures the crisp transmission of signals from one cell to another. When myelin tissue is damaged, communication between cells can be disrupted or even lost.

The most common myelin disorder is multiple sclerosis, a condition in which the body’s own immune system attacks and destroys myelin. The loss of myelin is also the hallmark of a family of serious and often fatal diseases known as pediatric leukodystrophies. While individually very rare, collectively several thousand children are born in the U.S. with some form of leukodystrophy every year.

The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.

However, several obstacles have thwarted scientists. One of the key challenges is that OPCs are a mature cell in the central nervous system and appear late in development.

"Compared to neurons, which are among the first cells formed in human development, there are more stages and many more steps required to create glial cells such as OPCs," said Goldman. "This process requires that we understand the basic biology and the normal development of these cells and then reproduce this precise sequence in the lab."

Another challenge has been identifying the ideal source of these cells. Much of the research in the field has focused on cells derived from tissue-specific and embryonic stem cells. While research using these cells has yielded critical insight into the biology of stem cells, these sources are not considered ideal to meet demand once stem cell-based therapies become more common.

The discovery in 2007 that human skin cells could be “reprogrammed” to the point where they returned to a biological state equivalent of an embryonic stem cell, called induced pluripotent stem cells, represented a new path forward for scientists. Because these cells – created by using the recipient’s own skin – would be a genetic match, the likelihood of rejection upon transplantation is significantly diminished. These cells also promised an abundant source of material from which to fashion the cells necessary for therapies.

Goldman’s team was the first to successfully master the complex process of using hiPSCs to create OPCs. This process proved time consuming. It took Goldman’s lab four years to establish the exact chemical signaling required to reprogram, produce, and ultimately purify OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.

Once they succeeded in identifying and purifying OPCs from hiPSCs, they then assessed the ability of the cells to make new myelin when transplanted into mice with a hereditary leukodystrophy that rendered them genetically incapable of producing myelin.

They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice.

"The new population of OPCs and oligodendrocytes was dense, abundant, and complete," said Goldman. "In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."

The next stage in evaluating these cells – clinical studies – may not be long in the offing. Goldman, along with a team of researchers and clinicians from Rochester, Syracuse, and Buffalo, are preparing to launch a clinical trial using OPCs to treat multiple sclerosis. This group, titled the Upstate MS Consortium, has been approved for funding by New York State Stem Cell Science (NYSTEM). While the consortia’s initial study – the early stages of which are scheduled to begin in 2015 – will focus cells derived from tissue sources, Goldman anticipates that hiPSC-derived OPCs will eventually be included in this project.

(Source: eurekalert.org)

Scientists at the Mainz University Medical Center have discovered another molecule that plays an important role in regulating myelin formation in the central nervous system. Myelin promotes the conduction of nerve cell impulses by forming a sheath around their projections, the so-called axons, at specific locations – acting like the plastic insulation around a power cord. The research team, led by Dr. Robin White of the Institute of Physiology and Pathophysiology at the University Medical Center of Johannes Gutenberg University Mainz, recently published their findings in the prestigious journal EMBO reports.

Complex organisms have evolved a technique known as saltatory conduction of impulses to enable nerve cells to transmit information over large distances more efficiently. This is possible because the specialized nerve cell axonal projections involved in conducting impulses are coated at specific intervals with myelin, which acts as an insulating layer. In the central nervous system, myelin develops when oligodendrocytes, which are a type of brain cell, repeatedly wrap their cellular processes around the axons of nerve cells forming a compact stack of cell membranes, a so-called myelin sheath. A myelin sheath not only has a high lipid content but also contains two main proteins, the synthesis of which needs to be carefully regulated.

The current study analyzed the synthesis of myelin basic protein (MBP), a substance which is essential for the formation and stabilization of myelin membranes. In common with all proteins, MBP is generated in a two-stage process originating from basic genetic material in the form of DNA. First, DNA is converted to mRNA, which, in turn, serves as a template for the actual synthesis of MBP. During myelin formation, the synthesis of MBP in oligodendrocytes is suppressed until distinct signals from nerve cells initiate myelination at specific “production sites”. To date, the mechanisms involved in the suppression of MBP synthesis over relatively long periods of time have not been understood. This is where the current work of the Mainz scientists comes in, as they were able to identify a molecule that is responsible for the suppression of MBP synthesis.

"This molecule, called sncRNA715, binds to MBP mRNA, thus preventing MBP synthesis," explains Dr. Robin White. "Our research findings show that levels of sncRNA715 and MBP inversely correlate during myelin formation and that it is possible to influence the extent of MBP production in oligodendrocytes by artificially modifying levels of sncRNA715. This indicates that the recently discovered molecule is a significant factor in the regulation of MBP synthesis."

Understanding the molecular basis for myelin formation is essential with regard to various neurological illnesses that involve a loss of the protective myelin layer. For example, it is still unclear why oligodendrocytes lose their ability to repair the damage to myelin in the progress of multiple sclerosis (MS). “Interestingly, in collaboration with our Dutch colleagues, we have been able to identify a correlation between levels of sncRNA715 and MBP in the brain tissue of MS patients,” Robin White continues. “In contrast with unaffected areas of the brain in which the myelin structure appears normal, there are higher levels of sncRNA715 in affected areas in which myelin formation is impaired. Our findings may help to provide a molecular explanation for myelination failures in illnesses such as multiple sclerosis.”

(Source: uni-mainz.de)

Research may prompt new investigations into white matter’s role in psychiatric disorders as well as connections between mood and myelin diseases, like MS

Animals that are socially isolated for prolonged periods make less myelin in the region of the brain responsible for complex emotional and cognitive behavior, researchers at the University at Buffalo and Mt. Sinai School of Medicine report in Nature Neuroscience online.

The research sheds new light on brain plasticity, the brain’s ability to adapt to environmental changes. It reveals that neurons aren’t the only brain structures that undergo changes in response to an individual’s environment and experience, according to one of the paper’s lead authors, Karen Dietz, PhD, research scientist in the Department of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences.

Dietz did the work while a postdoctoral researcher at Mt. Sinai School of Medicine; Jia Liu, PhD, a Mt. Sinai postdoctoral researcher, is the other lead author.

The paper notes that changes in the brain’s white matter, or myelin, have been seen before in psychiatric disorders, and demyelinating disorders have also had an association with depression. Recently, myelin changes were also seen in very young animals or adolescents responding to environmental changes.

"This research reveals for the first time a role for myelin in adult psychiatric disorders," Dietz says. "It demonstrates that plasticity in the brain is not restricted to neurons, but actively occurs in glial cells, such as the oligodendrocytes, which produce myelin."

(Source: eurekalert.org)

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