The remarkable discovery that axons or nerve cells can start degenerating spontaneously without prior damage to their protective myelin coating, and if found and treated early, this process can be reversed in mice, may lead to new effective treatments for multiple sclerosis (MS), according to the findings of a study published in Nature Medicine this week.

In the paper, senior authors Professor Martin Kerschensteiner of the Ludwig-Maximilians-Universität in Munich, Germany, and Professor Thomas Misgeld from the Technical University of Munich, and colleagues describe how they found a previously unknown type of axon or nerve cell degeneration, which they call “focal axonal degeneration” (FAD).

While the discovery opens the door to new drug targets, the researchers warn there is still a lot of work to be done before effective treatments are available, as Kerschensteiner explained to the press:

“As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates,” he cautioned.

Autoimmune diseases like MS occur when the immune system, which normally only targets and destroys foreign agents such as toxins, bacteria and viruses, that have entered the body, instead attacks the body’s own tissue, causing inflammation and eventually degeneration of the area affected.

In the case of MS, the immune system attacks the nervous system, resulting in damage to axons in the brain and spinal cord and slower or disrupted nerve signals.

The course of this common, and in many cases, disabling disease is often unpredictable with periods of remission interspersed with periods of relapse. As the damage becomes increasingly severe and affects more and more axons, there is increasing disruption and then even loss of sensory function, voluntary movement and bladder control.

The predominant view is that axon damage in MS follows the gradual destruction of the myelin sheath, the protective, electrically insulating coating of tissue surrounding the axon that speeds up the transmission of signals.

What triggers the axon damage itself, however, is poorly understood, and it was this that Kerschensteiner and Misgeld were trying to learn more about using lab mice when they made their surprising finding.

As Misgeld explained:

“We used an animal model in which a subset of axons is genetically marked with a fluorescent protein, allowing us to observe them directly by fluorescence microscopy.”

After injecting the mice with myelin (to activate the appropriate immune system response), the researchers found they started showing MS-like symptoms.

But they also found that many of the axons showing early signs of damage were still surrounded by an intact myelin coating. This gave them a hunch that myelin damage is not necessarily a prerequisite to axon damage.

Instead, they suggest a previously unrecognized mechanism, which they term “focal axonal degeneration (FAD)”, is responsible for the primary damage.

In their paper, they describe how FAD “is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation”.

They found that while most swollen axons stayed unchanged for several days, others recovered spontaneously, and that in the early stages, they could see FAD in axons with intact myelin sheaths.

This may explain why some patients with MS experience spontaneous remission of symptoms:

“In its early stages, axonal damage is spontaneously reversible,” said Kerschensteiner.

“This finding gives us a better understanding of the disease, but it may also point to a new route to therapy, as processes that are in principle reversible should be more susceptible to treatment.”

However, before any potential drugs can even be considered, never mind put forward for trial, we need a much better understanding of the underlying molecular chemistry and biology of a disease.

Previous studies of MS have already suggested that reactive oxygen and nitrogen radicals, chemicals produced by the immune system, play an important part in destroying axons. The researchers suggest in the case of FAD, these aggressive chemicals attack the mitchondria inside the nerve cells. Mitochondria are the “power cells” inside cells, they synthesize ATP molecules, the universal “currency units of energy” with which cells build, maintain and operate themselves.

“Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD,” write the researchers.

In the lab mice, they were able to neutralize ROS and RNS and rescue axons that had already started degenerating.

And in a final and equally exciting stage of their study, which involved co-authors based at the Universities of Göttingen and Geneva, they found characteristic signs consistent with FAD in brain tissue from human patients with MS, suggesting that the same treatment principles they established in the mice might also work in humans.

“In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy,” they write.

The reason why, even if this turns out to be the case, it will be a while before we have candidate drugs, is because the chemicals they used in the mice are not specific enough, and not tolerated enough to be of clinical use, also, as Kerschensteiner explained:

“Before appropriate therapeutic strategies can be developed, we need to clarify exactly how the damage arises at the molecular level.”

“We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis,” he added.

Funds from the Deutsche Forschungsgemeinschaft (DFG), the Emmy Noether Program, the Hertie Foundation and the Alexander von Humboldt Foundation helped finance the study.

“A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis.”
Ivana Nikić, Doron Merkler, Catherine Sorbara, Mary Brinkoetter, Mario Kreutzfeldt, Florence M Bareyre, Wolfgang Brück, Derron Bishop, Thomas Misgeld, Martin Kerschensteiner.
Nature Medicine Published online 27 March 2011

Additional source: Ludwig-Maximilians-Universität München (27 Mar 2011).

Written by: Catharine Paddock, PhD