Molecule PSR 1 Can Repair Damaged Nerve Cells

Today's post from sciencedaily.com (see link below) looks at the discovery of a unique 'wonder' molecule that can eliminate diseased cells but also apparently regenerate damaged nerve cells. The fact that it can re-join and fuse together broken axons in the central nervous system (frequent causes of neuropathic symptoms) is astonishing and has many implications for the future of neuropathy treatment. That said, as with so many of these findings, we're a long way from translating the theory into effective treatment models but take comfort from the fact that new discoveries are being made and will lead to improvements for future generations

Research findings have implications for regenerating damaged nerve cells 
Date:January 7, 2015 Source:University of Colorado at Boulder
 
Summary:

Two new studies have identified a unique molecule that not only gobbles up bad cells, but also has the ability to repair damaged nerve cells. Known as the phosphatidylserine receptor, or PSR-1, the molecule can locate and clear out apoptotic cells that are pre-programmed to die as well as necrotic cells that have been injured and are causing inflammation. Programmed cell death, or apoptosis, is a natural process that kills billions of cells in a typical human body each day.
 
Two new studies involving the University of Colorado Boulder and the University of Queensland (UQ) in Brisbane, Australia have identified a unique molecule that not only gobbles up bad cells, but also has the ability to repair damaged nerve cells.

Known as the phosphatidylserine receptor, or PSR-1, the molecule can locate and clear out apoptotic cells that are pre-programmed to die as well as necrotic cells that have been injured and are causing inflammation, said CU-Boulder Professor Ding Xue, who led one study and co-authored the other. Programmed cell death, or apoptosis, is a natural process that kills billions of cells in a typical human body each day.

But it is the finding that the PSR-1 molecule also can help reconnect and knit together broken nerve fibers, called axons, that has caught the attention of both science teams.

"I would call this an unexpected and somewhat stunning finding," said Xue of CU-Boulder's Department of Molecular, Cellular and Developmental Biology. "This is the first time a molecule involved in apoptosis has been found to have the ability to repair severed axons, and we believe it has great therapeutic potential."

Xue is the lead author on a paper being published Jan. 7 in Nature Communications that details how PSR-1 recognizes and removes cells that are pre-programmed to die or damaged. He also is co-author of the companion paper being published in Jan. 7 in Nature led by Associate Professor Massimo Hilliard of the UQ's Queensland Brain Institute that shows the major role played by PSR-1 in the regeneration of nerve axons, a holy grail of sorts for neurologists involved with patients who have suffered central nervous system damage from accidents or diseases.

Both studies relied on a popular lab organism known as C. elegans, a nearly microscopic nematode that is fast growing, translucent and has a sequenced genome showing that nearly half its genes are closely related to corresponding human genes.

"This will open new avenues to try and exploit this knowledge in other systems closer to human physiology and hopefully move toward solving injuries," said Hilliard. In the future, neurosurgery may be combined with molecular biology to deliver positive clinical outcomes and perhaps treat conditions like spinal cord or nerve injuries, he said.

During programmed cell death, apoptotic cells flag themselves for elimination by moving a specific cell membrane component known as phosphatidylserine (PS) from the inner membrane to the cell surface, setting them up to be engulfed. "These are what we call 'eat me' signals," said Xue.

In contrast, broken axons in nerve cells send PSR-1 molecules an SOS alert. "The moment there is a cut to the nerve cell we see a change in the cell membrane PS composition, which acts as a signal to PSR-1 molecules in the other part of the nerve that essentially says "I am in danger, come and save me," said Xue.

One of the most encouraging finding is that PSR-1 plays an early role in the axonal fusion process required for neuroregeneration, said Xue. "Whether human PSR has the capacity to repair injured axons is still unknown," he said. "But I think our new research findings will spur a number of research groups to chase this question."

While biomedical researchers have had some successes in repairing peripheral nerves and nerve clusters outside the brain and spinal cord in humans, there currently is no effective way to regenerate broken nerve cells in the central nervous system, said Xue. Such nerve damage can cause partial or total paralysis.

Xue, who first identified the PSR-1 receptor in 2003, said the collaboration between CU-Boulder and UQ has pushed scientific discovery forward. "We are trying to understand how PSR-1 removes cells through apoptosis and necrosis, and they are trying to understand if molecules involved in apoptosis also play a role in the neuroregeneration process," said Xue.

CU-Boulder postdoctoral researcher Yu-Zen Chen, a Nature Communications paper co-author, said the team currently is trying to find ways to raise the level of the PSR-1 in nematode cells, which likely would promote faster healing in nerve axons. "We think the higher the PSR-1 level, the higher the repair capacity of the molecule," said Chen.

Xue said C. elegans is an ideal organism to use in the hunt for new therapeutics to treat nerve damage because of its relatively small, well-known genome and short life span -- just a few days. "This makes drug screening much easier, faster and less expensive than using a mouse model, for instance," said Xue.

"The big finding is that we have a single receptor that does two different jobs," Xue said. "We don't have a solution yet for treating people with nerve damage, but we feel these findings offer promise in seeking new and effective therapeutics."

Story Source:

The above story is based on materials provided by University of Colorado at Boulder. Note: Materials may be edited for content and length.

Journal References:
Hengwen Yang, Yu-Zen Chen, Yi Zhang, Xiaohui Wang, Xiang Zhao, James I. Godfroy, Qian Liang, Man Zhang, Tianying Zhang, Quan Yuan, Mary Ann Royal, Monica Driscoll, Ning-Shao Xia, Hang Yin, Ding Xue. A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nature Communications, 2015; 6: 5717 DOI: 10.1038/ncomms6717
Brent Neumann, Sean Coakley, Rosina Giordano-Santini, Casey Linton, Eui Seung Lee, Akihisa Nakagawa, Ding Xue, Massimo A. Hilliard. EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature, 2015; 517 (7533): 219 DOI: 10.1038/nature14102

http://www.sciencedaily.com/releases/2015/01/150107122912.htm

3 D Digital Print Outs To Restore Damaged Nerves

Today's post from the always-reliable, sciencedaily.com (see link below) looks at the potential use of 3-D printed, custom silicone guides implanted with biochemical cues to help nerve regeneration after injury. Now this isn't the replacing of damaged nerves caused by any number of factors that we know of as being neuropathy (maybe later) but it is a major breakthrough with enormous potential. It's also not printing out digital 'plastic 'nerves' that could function as real ones - it's the placing of the right 'stimuli' between damaged nerve ends to encourage them to rejoin naturally. Of course, at the moment, experiments have only taken place on rats and who knows how long it will be before damaged nerves are regenerated in this way in humans but everybody living with neuropathy will be excited at the prospect of having a sort of, 'nerve transplant' in the same way that other organs of the body are currently transplanted. Science fiction? Not any more!

3-D printed guide helps regrow complex nerves after injury 
Date:September 18, 2015 Source:University of Minnesota

Summary:

Scientists have developed a first-of-its-kind, 3-D printed guide that helps regrow both the sensory and motor functions of complex nerves after injury. The groundbreaking research has the potential to help more than 200,000 people annually who experience nerve injuries or disease.


This is a 3-D printed nerve regeneration pathway implanted in a rat helped to improve walking in 10 to 12 weeks after implantation.
Credit: University of Minnesota College of Science and Engineering

A national team of researchers has developed a first-of-its-kind, 3D-printed guide that helps regrow both the sensory and motor functions of complex nerves after injury. The groundbreaking research has the potential to help more than 200,000 people annually who experience nerve injuries or disease.

Collaborators on the project are from the University of Minnesota, Virginia Tech, University of Maryland, Princeton University, and Johns Hopkins University.

Nerve regeneration is a complex process. Because of this complexity, regrowth of nerves after injury or disease is very rare, according to the Mayo Clinic. Nerve damage is often permanent. Advanced 3D printing methods may now be the solution.

In a new study, published today in the journal Advanced Functional Materials, researchers used a combination of 3D imaging and 3D printing techniques to create a custom silicone guide implanted with biochemical cues to help nerve regeneration. The guide's effectiveness was tested in the lab using rats.

To achieve their results, researchers used a 3D scanner to reverse engineer the structure of a rat's sciatic nerve. They then used a specialized, custom-built 3D printer to print a guide for regeneration. Incorporated into the guide were 3D-printed chemical cues to promote both motor and sensory nerve regeneration. The guide was then implanted into the rat by surgically grafting it to the cut ends of the nerve. Within about 10 to 12 weeks, the rat's ability to walk again was improved.

"This represents an important proof of concept of the 3D printing of custom nerve guides for the regeneration of complex nerve injuries," said University of Minnesota mechanical engineering professor Michael McAlpine, the study's lead researcher. "Someday we hope that we could have a 3D scanner and printer right at the hospital to create custom nerve guides right on site to restore nerve function."

Scanning and printing takes about an hour, but the body needs several weeks to regrow the nerves. McAlpine said previous studies have shown regrowth of linear nerves, but this is the first time a study has shown the creation of a custom guide for regrowth of a complex nerve like the Y-shaped sciatic nerve that has both sensory and motor branches.

"The exciting next step would be to implant these guides in humans rather than rats," McAlpine said. In cases where a nerve is unavailable for scanning, McAlpine said there could someday be a "library" of scanned nerves from other people or cadavers that hospitals could use to create closely matched 3D-printed guides for patients.

In addition to McAlpine, major contributors to the research team include Blake N. Johnson, Virginia Tech; Xiaofeng Jia, University of Maryland and Johns Hopkins University; and Karen Z. Lancaster, Esteban Engel, and Lynn W. Enquist, Princeton University.

This research was funded by grants from the National Institutes of Health, the Defense Advanced Research Projects Agency, the Maryland Stem Cell Research Fund, and the Grand Challenges Program at Princeton University.

To read more about the study entitled "3D Printed Anatomical Nerve Regeneration Pathways," visit the Advanced Functional Materials website.

Story Source:

The above post is reprinted from materials provided by University of Minnesota. Note: Materials may be edited for content and length.

Journal Reference: 
 
Blake N. Johnson, Karen Z. Lancaster, Gehua Zhen, Junyun He, Maneesh K. Gupta, Yong Lin Kong, Esteban A. Engel, Kellin D. Krick, Alex Ju, Fanben Meng, Lynn W. Enquist, Xiaofeng Jia, Michael C. McAlpine. 3D Printed Anatomical Nerve Regeneration Pathways. Advanced Functional Materials, 2015; DOI: 10.1002/adfm.201501760

http://www.sciencedaily.com/releases/2015/09/150918105030.htm

How the nerve is damaged

This description is something I can understand:-

Myelin Layer

The myelin layer is a white fatty and protein covering that insulates and protects a nerve fiber. The concept of myelin can be thought of as similar to the insulating coatings that typically surround electrical wiring. Just like insulators are needed to protect electrical wires, myelin is needed to protect our nerve fibers which incidentally, conduct electrical current also.

Myelin is made up of roughly about 80% fat, and about 20% protein. In addition to protecting our nerves, having a myelin covering or sheath allows nerve signals to be transported much quicker and more effectively. When the myelin sheath is damaged, impulses do not get transmitted through the nerve as quickly as it should. In addition, much like a damaged insulator covering can result in frayed wiring, a compromised myelin sheath can result in the underlying nerves becoming damaged as well. Neuropathy symptoms are often the result of this damage.

Originally from www.LivingWithPeripheralNeuropathy.com

Damaged Small Nerves Lead To Damaged Longer Nerves

Today's post from painnewsnetwork.org (see link below) covers a story that appeared about three weeks ago on this blog but this time it's much more understandable for the casual neuropathy reader. It talks about the discovery that the early symptoms of neuropathy that are often diagnosed as small fibre neuropathy, are in fact a warning signal of much greater deterioration of the longer nerves in the future. Many of you reading this will be having a 'duh' moment of 'So tell us something we didn't already know!' However, medical science likes things neatly packaged and labelled and the idea that small fibre neuropathy could lead to damage of other nerve sorts and much wider symptoms was not easily accepted. It was always thought that the longer nerves degraded first but these recent studies show that in fact it is just as likely that the short nerves begin the process leading to longer nerve degeneration. It's an interesting article which if you have any of the tingling, burning symptoms we're so accustomed too, may apply to you too.

Neuropathy More Damaging Than Previously Thought
By Pat Anson, Editor April 11, 2016
 
A tingling, sometimes painful sensation in the hands and feet – the early stages of small fiber neuropathy -- may be more damaging to the peripheral nervous system than previously thought, according to new research published in JAMA Neurology.

A 3-year study by Johns Hopkins neurologists found that patients with small fiber neuropathy showed unexpected deterioration over the entire length of sensory nerve fibers, not just nerve fibers at the surface of the skin.

“I liken small fiber neuropathy to the canary in the coal mine,” says senior author Michael Polydefkis, MD, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab. “It signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people’s quality of life. The results of this new study add urgency to the need for more screening of those with the condition and faster intervention.”

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association. Small fiber neuropathy can also be caused by lupus, HIV, Lyme disease, celiac disease or alcoholism.

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients feel pain or loss of feeling in their toes, feet, legs, hands and arms. It may also include a persistent burning, tingling or prickling sensation. The condition can eventually lead to injuries, chronic foot ulcers and even amputations.

Polydefkis and his colleagues found that small fiber nerve damage occurs even in patients with prediabetes, and the early symptoms of burning pain may be less benign than most clinicians think. Routine nerve tests, like nerve conduction, often fail to identify nerve damage because they mostly assess injury to large diameter nerve fibers.

In an effort to measure nerve damage more accurately, Johns Hopkins researchers took small samples of skin — the size of a large freckle — from 52 patients diagnosed with small fiber neuropathy and from 10 healthy controls. Skin samples were taken from the ankle, the lower thigh near the knee and the upper thigh. Three years later, samples from the same area in the same patients were taken for comparison.

Microscopic analysis of the skin samples showed that patients with small fiber neuropathy initially had fewer nerve fibers on the ankle compared to the upper thigh, demonstrating the most nerve damage was further down the leg. But after three years, researchers found that longer nerve fibers were also lost from the lower and upper thighs, something that was not expected.

“We are all taught in medical school that the longest nerves degrade first, and we show that this isn’t always the case,” says lead author Mohammad Khoshnoodi, MD, assistant professor of neurology at Johns Hopkins,

Patients with prediabetes or diabetes had at least 50 percent fewer small nerve fibers in their ankles initially than those participants with an unknown cause for their small fiber neuropathy, indicating these patients started the study with more damage to their small nerve fibers.

The patients with prediabetes continued to have worsening damage to their small nerve fibers over the course of the study, losing about 10 percent of their nerve fiber density each year at all sites tested along the leg. Patients with diabetes also lost similar rates of nerve fibers along the three sites of the leg.

“I expected that people with diabetes would do worse, but I didn’t really expect people with prediabetes to experience a similar rate of degradation of their small nerve fibers,” says Polydefkis.

Researchers caution that their study was small, and that other factors such as high blood sugar, smoking, high blood pressure and high cholesterol, may also have contributed to the decline in nerve fibers.

http://www.painnewsnetwork.org/stories/2016/4/11/neuropathy-more-damaging-than-previously-thought