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Stanford study first to show antibodies involved in nerve repair in injuries

June 15, 2010

Filed under: Uncategorized

In a new study conducted in mice, to be published online June 14 in Proceedings of the National Academy of Sciences, the Stanford scientists show for the first time that antibodies are critical to the repair of nerve damage to the peripheral nervous system — nervous tissue that extends outside the brain and spinal cord, such as the sciatic nerve, where circulating antibodies have access. The study also shows that some, but not all, antibodies get the job done. Harnessing those proteins’ unanticipated nurturing qualities may lead to new ways of repairing damage from stroke or spinal-cord injury, as well.

“Nobody has known why, but nerve cells in the central nervous system fail to regenerate after injury whereas those in the peripheral nervous system regenerate robustly,” said senior study author Ben Barres, MD, PhD, professor and chair of neurobiology. So his group was intrigued by one major difference between the two nervous systems: Antibodies, which are large bulky proteins, have limited access to the brain and spinal cord (these organs are surrounded by an interface called the blood-brain barrier or, in the spinal cord, the blood-spinal cord barrier), while they have ready access to the peripheral nervous system.

Nerve cells convey electrochemical impulses over long distances by means of long, tubular projections called axons. These axons are typically wrapped in an insulating layer of a fatty substance called myelin.

“After nerve injury, the degenerating myelin downstream from the injury is rapidly cleared in the peripheral, but not the central, nervous system,” said Barres. “In fact in an injured human brain or spinal cord, the degenerating myelin just sits there for the rest of the person’s lifetime. But after injury to, say, the sciatic nerve, the degenerating myelin is cleared within a week or less.”

The two first authors, Mauricio Vargas, MD, PhD, a former student in Barres’ lab, and Junryo Watanabe, PhD, a postdoctoral researcher in the lab, wondered whether antibodies to components of degenerating myelin might play a role in that clearance. The researchers obtained mutant laboratory mice that can’t make antibodies, and demonstrated that, in those mice, repair of injury to the sciatic nerve is substantially impeded, as is the removal of degenerating myelin downstream from the injury site. Simply injecting the injured mutant mice with antibodies from healthy, uninjured ones restored both myelin removal and sciatic-nerve repair capability in the mice.

While antibodies have been found to play a role in the disposal of aging red blood cells, this is the first time they’ve been implicated in injury repair, said Vargas, now in his internship at White Memorial Medical Center in Los Angeles pending the start of his residency in ophthalmology at UCLA.

What’s more, the investigators threw light on the way in which this happens. “We showed that antibodies grab onto degenerating myelin downstream from the site of the nerve injury, coating the myelin and tagging it for clearance by voracious immune cells called macrophages,” Vargas said.

The word macrophage roughly translates from Greek as “big eater.” These roving gourmands are especially prone to gobble up antibody-tagged bacteria and diseased cells. “It’s analogous to spreading cream cheese on a bagel,” said Vargas.

Using various standard laboratory tools, including special staining techniques, the study’s authors observed that macrophages do indeed chew up antibody-tagged degenerating myelin downstream from the nerve-injury site. Myelin clearance in the antibody-lacking mice was substantially enhanced when antibodies from healthy mice were provided.

Surprisingly, it made no difference whether the antibodies came from normal mice that had suffered similar injuries or mice that had suffered none. This suggests that the antibodies binding to degenerating myelin and flagging it for demolition by squads of macrophages are already present in uninjured mice, rather than summoned into service only after injury. These “off-the-shelf” natural antibodies save the week or two that it would have taken the body to generate the more sophisticated, precisely shaped antibodies that are produced in response to a particular viral or bacterial infection.

In an additional experiment, the Barres team injected the injured mice with a dose of an antibody that specifically targets a protein known to occur only on myelin. Doing so restored nerve-injury repair, whereas administering antibodies that bind to targets not associated with myelin didn’t help. This proved that not just any antibodies, but rather antibodies that associate with degenerating myelin, are the ones that expedite nerve repair in the peripheral nervous system.

It wouldn’t be helpful if naturally occurring antibodies were unable to distinguish between working and worthless myelin — this could result in debilitating autoimmune disease. But, Barres said, degenerating myelin has structural features on its surface that are quite different from those exposed to the immune system on the surface of functioning myelin.

Although these findings all involve the peripheral nervous system, they offer a tantalizing hint as to a possible way to instigate repair to damaged nerve cells in the central nervous system after, say, a stroke or spinal cord injury. “One idea,” said Barres, “would be to bypass the blood-brain barrier by delivering anti-degenerating-myelin proteins directly into the spinal fluid. We’re hoping that these antibodies might then coat the myelin, signaling to microglia — macrophages’ counterparts in the central nervous system — to clear the degenerating myelin.” That might, in turn, jump-start the regeneration of damaged nervous tissue, he added.

“This is really important, elegant work,” said Zhigang He, PhD, associate professor of neurology at Harvard Medical School whose lab focuses on the intrinsic regenerative ability of nervous tissue and who did not participate in the study but is familiar with it. “Everybody’s trying to understand what accounts for the difference between the capacities for repair in the peripheral versus the central nervous system. Now we have a possible mechanism, so we can start to think about some kind of strategy to speed up myelin clearance in the brain.”

Provided by Stanford University Medical Center

Nerves under control

May 13, 2010

Filed under: Uncategorized

The proper transmission of nerve signals along body nerves requires an insulation layer, named myelin sheath. To be efficient this sheath is designed to have a certain thickness and Swiss researchers from the ETH Zurich have now discovered that proteins Dlg1 and PTEN interact to control the myelin sheath thickness. Recently published in Science their discovery improves our understanding of Charcot-Marie-Tooth neurodegenerative diseases and open a new avenue in the potential treatment of these incurable and debilitating diseases.

A crucial factor in the transmission of nerve signals is the myelin layer – also known as the myelin sheath – which surrounds the axons. Axons are nerve cell projections through which the signals are relayed; the myelin sheath is formed by the Schwann cells in the peripheral nervous system, i.e. in the nervous system outside the brain and spinal chord. If it is too thick or too thin, the signal transmission slows down; if the myelin sheath becomes too badly damaged, it can cause diseases like Charcot-Marie-Tooth diseases. Patients suffer from an increasing weakness of the hands and feet, which gradually spreads to the arms and legs, sometimes even making them wheelchair-bound for the rest of their lives.

But which molecules regulate the thickness of the myelin sheath? Scientists at ETH Zurich from the research groups around biologists Ueli Suter and Nicolas Tricaud set about finding out. They have now published their findings in an online article in the journal Science.

The scientists didn’t have to start their search entirely from scratch, however, having already developed a mouse model for a sub-type of Charcot-Marie-Tooth disease; the model is based upon a mutation in the gene for the protein MTMR2 and leads to hypermyelination by the Schwann cells. What’s more, the researchers already knew from other studies that MTMR2 interacts with Dlg1.

In experiments conducted on cell cultures and the sciatic nerve in mice, the researchers were now able to demonstrate that Dlg1 inhibits myelin growth. For this to work, however, it needs to enlist the help of another signal protein: PTEN. Together, they ensure that the growth of the myelin sheath does not go to excess in the mouse’s development. If the brake is “released” by suppressing Dlg1 or PTEN, it results in myelin excess that not only leads to an extra-thick myelin sheath, but also to its degeneration. This process is characteristic of various diseases of the peripheral nervous system and , as it was revealed in the mouse model of Charcot-Marie-Tooth disease the Dlg-PTEN brake no longer works in these diseases. Nicolas Tricaud is convinced that the project helps to understand the basic molecular mechanisms of myelination, as well as offering new opportunities to define how the misdirection of these processes can cause neurodegenerative diseases and how this might be remedied.

More information: Cotter L, Ozçelik M, Jacob C, Pereira JA, Locher V, Baumann R, Relvas JB, Suter U, Tricaud N.: Dlg1-PTEN Interaction Regulates Myelin Thickness to Prevent Damaging Peripheral Nerve Overmyelination. Science. 2010 May 6. [Epub ahead of print] DOI:10.1126/science.1187735

Provided by ETH Zurich

“Nerves under control.” May 12th, 2010. www.physorg.com/news192908075.html

The neuropathic pain triad: neurons, immune cells and glia

February 5, 2008

Nat Neurosci. 2007 Nov;10(11):1361-8.
Scholz J, Woolf CJ.
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.

Dr. Zarife Sahenk to speak at Ohio State University Medical Center

February 17, 2005

Filed under: Uncategorized

Dr. Zarife Sahenk will be the keynote speaker at a seminar to be held at Ohio State University Medical Center in Columbus, Ohio on April 8th from 9 a.m. to 12 noon. The seminar will cover what is new in research and medical care for CMT, and what she forsees in the future.
In 2003, Dr. Sahenk proved that nerve growth factor NT-3 was successful in the first human trials for CMT nerve regeneration. Her study included 8 people. On October 21, 2003 she presented her findings and made CMT history at the Neurologist’s meeting in San Francisco.
Thanks go to CMTUS for the information.

U.S. Senate passes rare disease research measures

October 18, 2002

Filed under: Uncategorized

The House (last month) and the Senate (this Thursday) approved legislation that would double annual federal authorization for grants to companies to do research on rare diseases.
Call me cynical, but I think the administration did this to take the heat off them for not authorizing federal spending for stem cell research. Also, it’s peanuts, really. Double of practically nothing is still practically nothing. The bill authorizes expenditures of $25 million (up from $12 million) to research 6000 diseases that affect 25 million people. That’s $1 per person. Even MDA raises more than that: $58.3 million last year. (I’m not agitating for a larger slice of the pie here, mind you; I’m advocating a larger pie.)

Lorenzo’s oil finally proven to work

September 15, 2002

Filed under: Uncategorized

Lorenzo's OilThe medical establishment was skeptical, but Lorenzo’s oil has finally been proven to work. (For background on this story, I recommend the movie. The Myelin Project, started by the Odones, is still hard at work finding a way to replace lost myelin.

Another gene therapy success

September 14, 2002

Filed under: Uncategorized

Gene therapy has reached another milestone; it has been successfully used to treat a disorder affecting multiple organ systems throughout the body. So far it’s only been done on dogs, and young ones at that–plus there was only one gene that needed changing, whereas DS will require more than one to be changed–but this news "provides the strongest evidence yet that gene therapy could work against many different diseases"