Scientists in Oregon discovered the process behind a “bystander effect” phenomenon through which traumatic brain injury or disease can result in otherwise healthy nearby neurons temporarily shutting down and impairing nervous system function.
By experimenting with fruit flies, the researchers uncovered new roles for the molecule dSarm and glial cells in suppressing so-called “bystander neurons,” which could shed new light on how people lose cognitive function following such an injury.
“The question now, which I think is really interesting, is how much of that is truly due to damage, and how much of it is more of a bystander-type effect?” Marc Freeman, the study’s senior author and director of the Vollum Institute at Oregon Health and Science University, said in an interview with The Academic Times.
In a paper published in Neuron in December, Freeman and his OHSU colleagues detailed how when an injury occurs, the nervous system’s glial cells act as messengers to tell adjacent uninjured neurons to go dark, and how dSarm signaling can respond by temporarily shutting down neurons in an injured system.
Although the bystander effect is not a new phenomenon, it had never been demonstrated in a model organism, and, "The surprising thing was how strong that effect was,” Freeman said.
The researchers used the fruit fly Drosophila, a common model for neural networks in humans, to simulate a discrete head injury. In one example illustrating the bystander effect’s strength, the researchers snipped about 20 of nearly 300 neurons from an axon bundle, and the entire nerve shut down.
“It suggests that some part — and potentially a very large part — of functional loss in a patient could be otherwise healthy, intact neurons responding to these cues that are coming from the injured ones, and the bystanders are basically shutting down for a while even though they’re basically normal,” Freeman said.
The findings advance several years of thinking that dSarm acted as an axon depth molecule, meaning it drives neuron degeneration.
‘We were really surprised it was also doing this bystander thing, and we think that we now understand that,” Freeman said. “Sarm doesn't always kill neurons; sometimes it just stuns them in a reversible way. But if they’re severed, then it goes on to kill them.”
Freeman’s team also discovered the injury signal spreads through glia, less-studied nervous system cells whose important functions include maintaining ionic balance and acting as immune cells. Glia were already thought to be important for signaling broadly throughout the central nervous system to let neurons know what is going on.
This research determined that, with glial membranes separating and ensheathing axons in a nerve bundle, the injured neurons send a signal through the glia to the uninjured neurons.
“These glial cells are sort of the messengers that send the broad signal ‘Hey, there’s been an injury, everyone just pause,’” Freeman said. “‘Those of you who are injured, figure that out, go down the death pathway. Those of you that are healthy, give yourself a minute and recover and then you can go back to normal sensory function.’”
In a traumatic brain injury, axon degeneration doesn’t happen until about 24 hours later, Freeman explained, and the immediate effects on behavior that take place before that degeneration have been something of a mystery.
Those earlier effects might actually be due to bystander signaling via Sarm, Freeman posited, although that hypothesis must still be tested.
“This was one of my favorite papers we’ve had in a while, because it really changes the way I think about how an injury affects the nervous system,” Freeman said. “And it also, I think, should change how we start to think about injuries in the brain of a human, or a neurodegenerative disease.”
“If the bystander effect also applies in those situations — which obviously needs to be shown — that could mean that an enormous amount of functional loss in patients isn’t due to neurons degenerating, it's just they’re responding to that small group that's degenerating throughout the brain,” he continued. “And if that's true, we obviously need to find a way to work with that.”
In the future, Freeman wants to explore how exactly the activation of the Sarm pathway in a bystander neuron shuts down axon transport and sensory function in a reversible way.
“That's a really profound effect on a neuron,” he said, “and I think understanding how that happens is going to be pretty important.”
Additionally, Freeman would like to understand what signal is released by an injured neuron that tells glial cells to spread the word, and specifically how a glial cell tells a neuron to shut itself down.
“I will be shocked if that doesn’t teach us something interesting about some disease, or many diseases, just because it seems like a mechanism that would be involved in how the brain responds to trauma,” he said. “It is believed that the inflammatory effects of glia can compound many of these neurodegenerative diseases and make the situation worse.”
The study “Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia,” published Dec. 8 in Neuron, was authored by Jiun-Min Hsu, Yunsik Kang, Megan M. Corty, Danielle Mathieson, Owen M. Peters and Marc R. Freeman, Oregon Health and Science University.