Study identifies new target to preserve nerve function

July 14, 2017
Credit: CC0 Public Domain

Scientists in the Vollum Institute at OHSU have identified an enzyme that plays a crucial role in the degeneration of axons, the threadlike portions of a nerve cell that transmit signals within the nervous system. Axon loss occurs in all neurodegenerative diseases, so this discovery could open new pathways to treating or preventing a wide array of brain diseases.

The research team discovered a new role of the enzyme Axundead - or Axed - in promoting the self-destruction of . They found that when Axed was blocked, injured axons not only maintained their integrity but remained capable of transmitting signals within the brain's complex circuitry for weeks. Their research was published July 5 in the journal Neuron.

"If you target this pathway, you have a really good chance of preserving the functional aspects of neurons after a variety of types of trauma or injury," said senior author Marc Freeman, Ph.D., director of the Vollum Institute at OHSU. "It's a very attractive therapeutic target."

Freeman conducted the work in the Department of Neurobiology at the University of Massachusetts Medical School. He has since been recruited to head the Vollum Institute, which conducts cutting-edge basic research into how the nervous system works at a .

Severing axons, or axotomy, is a simple way to study the molecular basis of neurodegeneration as it leads to the activation of explosive . In the laboratory, researchers using this technique can identify pro-degenerative genes with great specificity, especially when using sophisticated genetic approaches in the fruit fly Drosophila, Freeman's primary research model organism. Drosophila shares these same pathways with humans. Previous work by Freeman's lab identified another enzyme, a gene called SARM, which was the first shown to activate a process that causes axons to disintegrate when damaged.

In the current study, Freeman and colleagues identified Axed, showed that it functions downstream of SARM to execute axonal degeneration, and, surprisingly, that the protection afforded by blocking Axed was even stronger than SARM.

"There was really nothing we could do to kill axons where Axed function was blocked," Freeman said.

From an evolutionary perspective, Freeman said SARM and Axed function are likely important in the peripheral nervous system after injury because programmed axon death allows for efficient packaging of damaged cellular materials for removal by immune cells. This process thereby clears the pathway for new neuronal processes to regrow, reinnervate tissues, and recover function.

From a therapeutic perspective, the goal of the work is to understand at the molecular level how axons degenerate, and block those pathways in patients to preserve nervous system function. In many nervous system injuries axons are not severed but become stretched or crushed, which activates the SARM-dependent death program and drives axon loss. In those cases, it's imperative to block SARM and Axed signaling to preserve axon integrity, and in turn neuronal function. At the same time, Freeman and others have shown that SARM-dependent signaling pathways also drive axon loss in neurodegenerative conditions including glaucoma, traumatic brain injury and peripheral neuropathy. This suggests the notion of an ancient and conserved axon death signaling pathway that is widely activated to drive axon loss. Since axon loss is a universal feature of neurodegenerative diseases, it seems likely that blocking this could have enormous therapeutic benefit.

"If we can find ways to block it, maybe we can preserve function in a wide array of patients who have lost axons through or other neural trauma," Freeman said.

Explore further: A fly mutation suggests a new route for tackling ALS

More information: Lukas J. Neukomm et al, Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly, Neuron (2017). DOI: 10.1016/j.neuron.2017.06.031

Related Stories

A fly mutation suggests a new route for tackling ALS

April 8, 2013
A team of researchers, led by Marc Freeman, PhD, an early career scientist with the Howard Hughes Medical Institute and associate professor of neurobiology at the University of Massachusetts Medical School have discovered ...

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 ...

Axon regeneration in response to nervous system injury

May 4, 2017
Alexandra Byrne, PhD, assistant professor of neurobiology, is working to identify which genes control how the nervous system responds to injury. Specifically, the Byrne lab at UMMS is working to identify the genes that prevent ...

Researchers discover how neurons tell each other to die under trauma, disease

March 9, 2017
A major contributor to most neurological diseases is the degeneration of a wire-like part of nerve cells called an axon, which electrically transmits information from one neuron to another. The molecular programs underlying ...

Findings suggest ways to block nerve cell damage in neurodegenerative diseases

March 23, 2017
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 ...

Study overturns seminal research about the developing nervous system

April 20, 2017
New research by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA overturns a long-standing paradigm about how axons—thread-like projections that connect cells in the ...

Recommended for you

Intermittent fasting found to increase cognitive functions in mice

December 12, 2017
(Medical Xpress)—The Daily Mail spoke with the leader of a team of researchers with the National Institute on Aging in the U.S. and reports that they have found that putting mice on a diet consisting of eating nothing every ...

Neuroscientists show deep brain waves occur more often during navigation and memory formation

December 12, 2017
UCLA neuroscientists are the first to show that rhythmic waves in the brain called theta oscillations happen more often when someone is navigating an unfamiliar environment, and that the more quickly a person moves, the more ...

How Zika virus induces congenital microcephaly

December 12, 2017
Epidemiological studies show that in utero fetal infection with the Zika virus (ZIKV) may lead to microcephaly, an irreversible congenital malformation of the brain characterized by an incomplete development of the cerebral ...

Presurgical imaging may predict whether epilepsy surgery will work

December 11, 2017
Surgery to remove a part of the brain to give relief to patients with epilepsy doesn't always result in complete seizure relief, but statisticians at Rice University have developed a method for integrating neuroimaging scans ...

Selecting sounds: How the brain knows what to listen to

December 11, 2017
How is it that we are able—without any noticeable effort—to listen to a friend talk in a crowded café or follow the melody of a violin within an orchestra?

Scientists discover new way to help nerve regeneration in spinal cord injury

December 11, 2017
There is currently no cure for spinal cord injury or treatment to help nerve regeneration so therapies offering intervention are limited. People with severe spinal cord injuries can remain paralysed for life and this is often ...

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.