Findings suggest ways to block nerve cell damage in neurodegenerative diseases

March 23, 2017
Nerve axons (left) serve as the electrical wiring of the nervous system. Scientists have implicated a specific molecule in triggering a self-destruct program in axons that leads to their degeneration (right). Since axonal degeneration is a common thread in many neurodegenerative diseases, including peripheral neuropathy, researchers are seeking ways to block it. Both images show mouse axons. Yellow and green color added for clarity. Credit: Josiah Gerdts/ Milbrandt lab

In many neurodegenerative conditions—Parkinson's disease, amyotrophic lateral sclerosis (ALS) and peripheral neuropathy among them—an early defect is the loss of axons, the wiring of the nervous system. When axons are lost, nerve cells can't communicate as they should, and nervous system function is impaired. In peripheral neuropathy in particular, and perhaps other diseases, sick axons trigger a self-destruct program.

In new research, scientists at Washington University School of Medicine in St. Louis have implicated a specific molecule in the self-destruction of . Understanding just how that damage occurs may help researchers find a way to halt it.

The study is published March 22 in the journal Neuron.

"Axons break down in a lot of neurodegenerative diseases," said senior author Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. "Despite the fact these diseases have different causes, they are all likely rooted in the same pathway that triggers axon degeneration. If we could find a way to block the pathway, it could be beneficial for many different kinds of patients."

Since the molecular pathway that leads to loss of axons appears to do more harm than good, it's not clear what role this self-destruct mechanism plays in normal life. But scientists suspect that if the pathway that destroys axons could be paused or halted, it would slow or prevent the gradual loss of nervous system function and the debilitating symptoms that result. One such condition, , affects about 20 million people in the United States. It often develops following chemotherapy or from nerve damage associated with diabetes, and can cause persistent pain, burning, stinging, itching, numbness and muscle weakness.

"Peripheral neuropathy is by far the most common neurodegenerative disease," said co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology. "Patients don't die from it, but it has a huge impact on quality of life."

In previous studies, Stefanie Geisler, MD, an assistant professor of neurology, working with DiAntonio and Milbrandt, showed that blocking this axon self-destruction pathway prevented the development of peripheral neuropathy in mice treated with the chemotherapy agent vincristine. The hope is that if methods are developed to block this pathway in people, then it might be possible to slow or prevent the development of neuropathy in patients.

Toward that end, the Milbrandt and DiAntonio labs showed that a molecule called SARM1 is a central player in the self-destruct pathway of axons. In healthy neurons, SARM1 is present but inactive. For reasons that are unclear, injury or disease activate SARM1, which sets off a series of events that drains a key cellular fuel—called nicotinamide adenine dinucleotide (NAD)—and leads to destruction of the axon. Though the researchers previously had shown SARM1 was required for this chain of events to play out, the details of the process were unknown.

SARM1 and similar —those containing what are called TIR domains—most often are studied in the context of immunity, where these domains serve as scaffolds. Essentially, TIR domains provide a haven for the assembly of molecules or proteins to perform their work.

The researchers had assumed that SARM1 acted as a scaffold to provide support for the work of destroying axons, beginning with the rapid loss of cellular fuel that occurs minutes after SARM1 becomes active. The scientists set about searching for the demolition crew—the active molecule or molecules that use the SARM1 scaffold to carry out the demolition. The study's first author, Kow A. Essuman, a Howard Hughes Medical Institute Medical Research Fellow and an MD/PhD student in Milbrandt's lab, performed a litany of cellular and biochemical experiments searching for the demolition crew and came up empty.

"We performed multiple experiments but could not identify molecules that are traditionally known to consume NAD," Essuman said.

But as a last resort, the investigators tested SARM1 itself. To their great surprise, they found it was doing more than simply providing a passive platform. Specifically, the researchers showed SARM1's TIR domain acts as an enzyme, a molecule that carries out biochemical reactions, in this case destroying axons by first burning all their NAD cellular fuel.

"There are more than 1,000 papers describing the function of proteins containing TIR domains," DiAntonio said. "No one had ever shown that this type of molecule could be an enzyme. So we went into our experiments assuming SARM1 was only a scaffold and that there must be some other enzyme responsible for demolition of the axon. We essentially searched for a demolition crew, only to discover that the scaffold itself is destroying the structure. It's the last thing you would expect."

The findings suggest molecules similar to SARM1—those with TIR domains and known to serve as scaffolds in the immune system—may prove to have additional functions that go beyond their structural roles. The research also invites a search for drugs that block the SARM1 enzyme from triggering axonal destruction.

Explore further: Major pathway identified in nerve cell death offers hope for therapies

More information: Kow Essuman et al. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD +Cleavage Activity that Promotes Pathological Axonal Degeneration, Neuron (2017). DOI: 10.1016/j.neuron.2017.02.022

Related Stories

Major pathway identified in nerve cell death offers hope for therapies

April 23, 2015
New research highlights how nerves - whether harmed by disease or traumatic injury - start to die, a discovery that unveils novel targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative ...

Study detailing axonal death pathway may provide drug targets for neurodegenerative diseases

January 22, 2015
Axons connect neurons with each other to form the neural networks that underpin the vital functions of perception, motility, cognition, and memory. In many neurodegenerative disorders, from traumatic injury or toxic damage ...

Scientists identify first gene in programmed axon degeneration

June 7, 2012
Degeneration of the axon and synapse, the slender projection through which neurons transmit electrical impulses to neighboring cells, is a hallmark of some of the most crippling neurodegenerative and brain diseases such as ...

Scientists show how nerve wiring self-destructs

May 9, 2013
Many medical issues affect nerves, from injuries in car accidents and side effects of chemotherapy to glaucoma and multiple sclerosis. The common theme in these scenarios is destruction of nerve axons, the long wires that ...

Molecule shown to repair damaged axons

March 8, 2017
A foray into plant biology led one researcher to discover that a natural molecule can repair axons, the thread-like projections that carry electrical signals between cells. Axonal damage is the major culprit underlying disability ...

Recommended for you

The neural codes for body movements

July 21, 2017
A small patch of neurons in the brain can encode the movements of many body parts, according to researchers in the laboratory of Caltech's Richard Andersen, James G. Boswell Professor of Neuroscience, Tianqiao and Chrissy ...

Faulty support cells disrupt communication in brains of people with schizophrenia

July 20, 2017
New research has identified the culprit behind the wiring problems in the brains of people with schizophrenia. When researchers transplanted human brain cells generated from individuals diagnosed with childhood-onset schizophrenia ...

Scientists discover combined sensory map for heat, humidity in fly brain

July 20, 2017
Northwestern University neuroscientists now can visualize how fruit flies sense and process humidity and temperature together through a "sensory map" within their brains, according to new research.

Scientists reveal how patterns of brain activity direct specific body movements

July 20, 2017
New research by Columbia scientists offers fresh insight into how the brain tells the body to move, from simple behaviors like walking, to trained movements that may take years to master. The discovery in mice advances knowledge ...

Team traces masculinization in mice to estrogen receptor in inhibitory neurons

July 20, 2017
Researchers at Cold Spring Harbor Laboratory (CSHL) have opened a black box in the brain whose contents explain one of the remarkable yet mysterious facts of life.

Speech language therapy delivered through the Internet leads to similar improvements as in-person treatment

July 20, 2017
Telerehabilitation helps healthcare professionals reach more patients in need, but some worry it doesn't offer the same quality of care as in-person treatment. This isn't the case, according to recent research by Baycrest.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.