Study identifies new target to preserve nerve function

July 14, 2017

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 axons. They found that when Axed function 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 molecular level.

Severing axons, or axotomy, is a simple way to study the molecular basis of neurodegeneration as it leads to the activation of explosive axonal degeneration. 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 pathway 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 neurodegenerative diseases or other neural trauma," Freeman said.
-end-
Lead author Lukas J. Neukomm, Ph.D., was supported by the Charles A. King Trust Postdoctoral Fellowship, supported by the Harold Whitworth Pierce Charitable Trust. Freeman's work on the study was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, grant R01 NS053538. During the period of the study, Freeman was an investigator with the Howard Hughes Medical Institute.

Oregon Health & Science University

Related Neurodegenerative Diseases Articles from Brightsurf:

Bringing drugs to the brain with nanoparticles to treat neurodegenerative diseases
Researchers from the Institut national de la recherche scientifique (INRS) have shown that nanoparticles could be used to deliver drugs to the brain to treat neurodegenerative diseases.

First 'pathoconnectome' could point toward new treatments for neurodegenerative diseases
Scientists from the John A. Moran Eye Center at the University of Utah have achieved another first in the field of connectomics, which studies the synaptic connections between neurons.

Unlocking the mystery of tau for treatment of neurodegenerative diseases
A team of researchers from various collaborating universities and hospitals in Japan has uncovered crucial molecular details regarding the activity of the ''tau'' protein, promising to revolutionize the therapy of tau-induced neurodegenerative diseases.

Investigational drug stops toxic proteins tied to neurodegenerative diseases
An investigational drug that targets an instigator of the TDP-43 protein, a well-known hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), may reduce the protein's buildup and neurological decline associated with these disorders, suggests a pre-clinical study from researchers at Penn Medicine and Mayo Clinic.

Inhibition of sphingolipid metabolism and neurodegenerative diseases
Disrupting the production of a class of lipids known as sphingolipids in neurons improved symptoms of neurodegeneration and increased survival in a mouse model.

How understanding the dynamics of yeast prions can shed light on neurodegenerative diseases
How understanding the dynamics of yeast prions can shed light on neurodegenerative diseases

New family of molecules to join altered receptors in neurodegenerative diseases
An article published in the Journal of Medicinal Chemistry shows a new family of molecules with high affinity to join imidazoline receptors, which are altered in the brain of those patients with neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's.

Examining diagnoses of stress-related disorders, risk of neurodegenerative diseases
Researchers investigated how stress-related disorders (such as posttraumatic stress disorder, adjustment disorder and stress reactions) were associated with risk for neurodegenerative diseases, including Alzheimer and Parkinson disease and amyotrophic lateral sclerosis (ALS), using data from national health registers in Sweden.

Toxic protein, linked to Alzheimer's and neurodegenerative diseases, exposed in new detail
The protein tau has long been implicated in Alzheimer's and a host of other debilitating brain diseases.

Study uncovers unexpected connection between gliomas, neurodegenerative diseases
New basic science and clinical research identifies TAU, the same protein studied in the development of Alzheimer's, as a biomarker for glioma development.

Read More: Neurodegenerative Diseases News and Neurodegenerative Diseases Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.