October 4, 2016

Story and photo by Rebecca Hood

September's featured paper, "Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper" in Cell Reports, is published by a team of researchers led by Mary Logan, Ph.D., assistant professor of neurology, OHSU School of Medicine (pictured, right in photo), Sean Speese, Ph.D., assistant professor of neurology, OHSU School of Medicine (pictured, left). Dr. Logan's current graduate student Maria Purice (pictured, middle) and former student Derek Mushashe, Ph.D. (not pictured), also contributed to the paper.

"We used to think that glia were just the 'glue' that held the nervous system together," said Mary Heinricher, Ph.D., associate dean for basic research, OHSU School of Medicine, who selected this month's paper. "Although we now know that is not the case, there is still a lot to learn about what glia do and how neurons and glia interact. I was intrigued by the evidence from this paper that the insulin-like signaling pathway could have a fundamental role in linking injury of an axon to recruitment of glia as part of a neuroprotective mechanism."

Glial cells

Glial cells are staunch defenders of brain health, but there is still a great deal to learn about how glia detect various forms of trauma in the nervous system. 

"Glial responses can provide robust neuroprotection, but we still don't understand how glia recognize that a neuron has been damaged," explained Dr. Logan. "What are the injury cues released by a degenerating neuron? How do glia sense these cues? Finally, what are the molecular cascades that govern important neuroprotective responses to neural injury?"

Brain of the fruit fly

In order to investigate the mechanisms that underlie glial immune activity, Dr. Logan and her lab use Drosophila melanogaster, commonly known as fruit flies, as a powerful model organism. 

"Previous work from other labs has shown that the basic mechanisms of neuronal death and glial responses to neurodegeneration are conserved across species," says Dr. Logan. "Specifically, when you cut the nerve of an adult fly, axons undergo an intrinsic Wallerian degeneration program that mirrors what happens in other species, including humans." 

Forced expression of specific molecules in mammalian neurons delays axonal degeneration in a variety of injury and disease contexts, and the same molecules block Wallerian degeneration in adult fly axons. These studies, combined with the powerful genetic prowess of the fly, make this an ideal system to investigate how neurons die.

In animals ranging from flies to humans, glia respond swiftly and dramatically to degenerating axons by extending membranes into areas of injury and phagocytosing, or engulfing, degenerating axonal material. Scientists have identified only a handful of molecules involved in this response in flies, but the best studied is a glial engulfment receptor called Draper. 

"Draper is a highly conserved receptor required for Drosophila glia to phagocytose severed axons and synaptic material," explained Dr. Logan. "The related mammalian gene (MEGF10) is also essential for glial engulfment of dying neurons and degenerating projections in rodents."

Discovering signaling pathways

Using a well-established injury model in which the olfactory nerves are severed in adult fruit flies, Dr. Logan's group, along with collaborator Dr. Sean Speese, discovered that the insulin-like signaling pathway is acutely activated in local glia in response to axon degeneration. 

"More specifically," she explained, "activation of the Insulin-like Receptor in glia within hours after axon injury is required for glia to increase the production of Draper and, thus, infiltrate damaged areas of the brain to clear away neuronal debris. Our work now points to insulin-like signaling as a novel local communication relay between neurons and glia that initiates critical glial immune cascades."

This discovery is significant because it reveals a new set of factors that glia likely recognize as injury cues. 

Dr. Logan said, "Our research is the first to implicate insulin-like signaling as a mechanism for triggering glial immunity in the adult brain. Notably, because insulin-like signaling cascades and Draper/MEGF10 are conserved, we propose that our work in Drosophila will provide new insight into how insulin and related factors, for example the insulin-like growth factor, IGF, are coupled to glial responses to neural injury in mammals."

"Pressing future questions"

This discovery has generated a number of new questions. 

"First, there are several neuropeptide ligands that may be released from injured axons, as well as other glial cells, to active the insulin-like receptor on responding glia. What are those ligands? How are those ligands released?" said Dr. Logan. 

Additionally, while glial activation is generally neuroprotective, Dr. Logan describes instances such as chronic neurological disease or advanced age when the glial response is "overexuberant" and can exacerbate damage. 

These new findings will now encourage neuroscientists to reframe how they view the role of insulin-like pathways in the context of neurodegeneration. In the future, for example, targeted therapies may be developed to either increase or decrease activation of insulin-like signaling cascades in different disease and injury contexts.