Glial transcriptional activation is downstream of axon degeneration and Draper signaling.
In response to brain injury, cells in the nervous system swiftly coordinate events that promote survival and repair. Glial cells—the most abundant cells in the nervous system—quickly locate the trauma site, clear damaged neurons, and recruit extra immune cells.
This cascade of glial cells’ reactive events is promoted by Draper, an engulfment receptor needed to recognize and clear cellular debris in fruit flies, roundworms, and mammals. Until recently, the pathways that mediate glia responses to injury have been poorly defined. Injury signals from damaged cells that trigger glia receptors had been presumed to drive glia reactions. But, whether and how cellular debris activated glial transcriptional responses remained mechanistically unclear.
Now, a team led by OHSU scientists has identified a gene that responds to injury signals by binding to Draper and initiates and coordinates intracellular signaling pathways. This gene, TRAF4, provides scientists with important information about the pathways that spur glial cells to recognize and clear degenerating axons. Marc Freeman, Ph.D., director and senior scientist at the Vollum Institute, and Mary Logan, Ph.D., assistant scientist and assistant professor of neurology at the Jungers Center for Neurosciences Research, led the research, which was published in Nature Communications.
The study found that Draper is required by each cell to activate response to injury. The team’s work supports a model in which axon trauma activates Draper, which in turn promotes signaling through Draper’s newly identified binding partner and activates a series of events that contributes to human disease.
Glia reaction is accompanied by the quick release of two glia subtypes—GFAP and S100β. The upregulation of these subtypes is one of the earliest detectable changes in neural tissues after brain injury. These increases are seen in neurological diseases, such as Alzheimer’s and autism.
Logan and her research were featured on the OHSU YouTube channel on March 8.
In addition to Freeman and Logan, the multi-institutional team that conducted the research published in Nature Communications included Tsai-Yi Lu, Ph.D., at Johns Hopkins University and, from the University of Massachusetts Medical School, Jennifer MacDonald, M.D., Ph.D., Lukas Neukomm, Ph.D., Amy Sheehan, and Rachel Bradshaw. This work was supported by NIH RO1 NS053538 to Freeman, who was also an investigator with the Howard Hughes Medical Institute during the period of this study.