Summary: According to researchers, axons coordinate each other’s destruction, contributing to neurodegeneration.
Source: University of Virginia.
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 axon degeneration are therefore important targets for therapeutic intervention – the idea being that if axons can be preserved, rather than allowed to die in diseased conditions, then loss of critical processes like movement, speech or memory will be slowed.
For more than 150 years, researchers believed that axons died independently of one another when injured as a result of trauma, such as stroke or brain injury, or of a neurological disease, such as Alzheimer’s.
But a new study by University of Virginia researchers challenges this idea and suggests that axons coordinate each other’s destruction, thereby contributing to the degeneration that makes neurological diseases so devastating and permanent.
The paper appears in the March 20 issue of the journal Current Biology.
“We are the first to demonstrate that a receptor known to convey information from the outside of the cell to the inside of the cell is essential for axon degeneration after injury,” said study co-author Christopher Deppmann, a UVA biology, neuroscience, cell biology and biomedical engineering professor. “This implies that axons talk to each other while they are dying, and an injured axon can coax an uninjured neighbor to die, too.”
This creates a ripple effect of neuron death that confounds efforts to restore the growth of healthy cells. However, the researchers also found that the death spiral can be slowed when this communication is blocked using a laboratory method that could inspire pharmacological therapies to treat pathological axon degeneration. The method demonstrates that injured axons can be preserved for at least 10 times longer when their communication with neighbors is blocked.
“This represents a paradigm shift for how we think about the ways the nervous system is torn apart during pathology,” Deppmann said. “It opens a possible new avenue for the development of therapies that may be promising for slowing or stopping the effects of Alzheimer’s disease, traumatic brain injury and spinal cord injury.”
Deppmann and his graduate student, Kanchana Gamage, the study’s lead author, believe that axons communicate the death message to each other during injury as a leftover activity, “borrowed” from the nervous system’s developmental period when axons are overproduced and then improper or unnecessary connections are eliminated by a similar communication between axons. While this process is essential during development, it appears to be hijacked in diseased or traumatic conditions to reactivate and accelerate neuron degeneration.
The researchers have found that axons receive the message to die as a chemical signal via a cell surface receptor known as “death receptor 6.” They speculate that this chemical signal is released from the axon itself, and they currently are working to determine the identity of this chemical signal.
“Knowing this, it may be possible that for diseases such as Alzheimer’s and Parkinson’s, a drug could be developed to block the axon receptors from receiving the specific message that leads to degeneration,” Gamage said. “If so, the damage to healthy cells could be slowed or stopped. Essentially, we could tell axons not to pick up the phone if a degeneration signal is on the other line.”
Funding: The National Institutes of Health supported the research, which was conducted by investigators in UVA’s biology and psychology departments and Neuroscience Graduate Program, as well as at James Madison University.
Source: Fariss Samarrai – University of Virginia
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons” by Kanchana K. Gamage, Irene Cheng, Rachel E. Park, Mardeen S. Karim, Kazusa Edamura, Christopher Hughes, Anthony J. Spano, Alev Erisir, and Christopher D. Deppmann in Current Biology. Published online January 30 2017 doi:10.1016/j.cub.2017.01.062
[cbtabs][cbtab title=”MLA”]University of Virginia “Researchers Discover How Neurons Tell Each Other to Die Under Trauma and Disease.” NeuroscienceNews. NeuroscienceNews, 10 March 2017.
<https://neurosciencenews.com/neuron-apoptosis-trauma-6230/>.[/cbtab][cbtab title=”APA”]University of Virginia (2017, March 10). Researchers Discover How Neurons Tell Each Other to Die Under Trauma and Disease. NeuroscienceNew. Retrieved March 10, 2017 from https://neurosciencenews.com/neuron-apoptosis-trauma-6230/[/cbtab][cbtab title=”Chicago”]University of Virginia “Researchers Discover How Neurons Tell Each Other to Die Under Trauma and Disease.” https://neurosciencenews.com/neuron-apoptosis-trauma-6230/ (accessed March 10, 2017).[/cbtab][/cbtabs]
Abstract
Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons
Highlights
•DR6 has a modest role in developmental axon degeneration
•DR6 is required for Wallerian degeneration in vitro and in vivo
•Axon degeneration and demyelination can be mechanistically uncoupled post-injury
•DR6 is required for the activation of classic Wallerian degeneration pathways
Summary
Axon degeneration during development is required to sculpt a functional nervous system and is also a hallmark of pathological insult, such as injury. Despite similar morphological characteristics, very little overlap in molecular mechanisms has been reported between pathological and developmental degeneration. In the peripheral nervous system (PNS), developmental axon pruning relies on receptor-mediated extrinsic degeneration mechanisms to determine which axons are maintained or degenerated. Receptors have not been implicated in Wallerian axon degeneration; instead, axon autonomous, intrinsic mechanisms are thought to be the primary driver for this type of axon disintegration. Here we survey the role of neuronally expressed, paralogous tumor necrosis factor receptor super family (TNFRSF) members in Wallerian degeneration. We find that an orphan receptor, death receptor 6 (DR6), is required to drive axon degeneration after axotomy in sympathetic and sensory neurons cultured in microfluidic devices. We sought to validate these in vitro findings in vivo using a transected sciatic nerve model. Consistent with the in vitro findings, DR6−/− animals displayed preserved axons up to 4 weeks after injury. In contrast to phenotypes observed in Wlds and Sarm1−/− mice, preserved axons in DR6−/− animals display profound myelin remodeling. This indicates that deterioration of axons and myelin after axotomy are mechanistically distinct processes. Finally, we find that JNK signaling after injury requires DR6, suggesting a link between this novel extrinsic pathway and the axon autonomous, intrinsic pathways that have become established for Wallerian degeneration.
“Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons” by Kanchana K. Gamage, Irene Cheng, Rachel E. Park, Mardeen S. Karim, Kazusa Edamura, Christopher Hughes, Anthony J. Spano, Alev Erisir, and Christopher D. Deppmann in Current Biology. Published online January 30 2017 doi:10.1016/j.cub.2017.01.062
