Microglia Use Novel 'Skoupocytosis' Process to Clear Neuronal Waste

Inside the brain, neurons generate waste constantly—damaged proteins, worn-out organelles, the cellular detritus of thinking and firing. Most of the time, neurons handle this themselves, packaging garbage into specialized compartments and either ejecting it into surrounding space or shuttling it back to the cell body for disposal. But sometimes the system backs up. In stressed or overactive neurons, these waste-filled organelles can swell so large they cannot squeeze through the narrow confines of an axon. When that happens, the neuron appears to call for help.

Researchers at Johns Hopkins University have identified a previously unknown cleanup mechanism they call skoupocytosis—a process in which immune cells called microglia physically extract accumulated waste from neurons that cannot clear it on their own. The work, posted as a preprint in July, reveals what amounts to a distress signal and a rescue operation happening continuously in the living brain.

Microglia are the brain's professional scavengers. They patrol neural tissue, consuming debris and damaged proteins. What the new research shows is that they can do something more targeted: they can make direct contact with axons and selectively remove large organelles packed with degraded proteins. Shigeki Watanabe, the study's lead investigator and a cell biology professor at Johns Hopkins, explains that neurons have multiple waste-disposal routes, but occasionally those routes become congested. When they do, microglia appear to step in.

The team first observed this behavior in cell cultures, watching microglia engulf organelle clumps from neurons. But culture dishes are artificial environments. Microglia behave differently outside the brain—they lose their characteristic branched shape and take on an amoeba-like form. To publish the work, Watanabe says, they needed to see the same process happening in living brain tissue. That required years of technical development. Renee Pepper, a postdoctoral researcher in Watanabe's lab, describes the work as "imaging blindly"—searching through three-dimensional brain tissue for the precise moment when a microglia cell encounters a neuronal organelle.

When they found it, the pattern was clear. In the somatosensory cortex of living mice, microglia extended their branched processes toward an average of 77 percent of stationary organelles during 15-minute imaging sessions. Over several minutes, a microglia process would touch an organelle, pull back, then return again. After these repeated contacts, fluorescent markers showed that material from the neuron's waste organelles had moved into the microglia. The researchers named this interaction skoupocytosis—from the Greek word for "scooping."

The mechanism appears to rely on a molecular signal. When neurons are stimulated, they produce high levels of an enzyme called ABHD16A, which regulates the release of a signaling molecule called phosphatidylserine. When researchers blocked this enzyme, phosphatidylserine levels dropped outside the cell, organelles accumulated larger in neurons, and the cleanup process stalled. This suggests that phosphatidylserine acts as a distress flag—a molecular way for neurons to tell microglia that waste is piling up and needs removal. Nicole Scott-Hewitt, an assistant professor at Duke University who was not involved in the study, notes that this finding indicates microglia do not indiscriminately consume neuronal debris but instead respond to specific chemical cues. The discovery adds to a growing understanding of how neurons and microglia communicate through molecular language.

The work raises questions that remain unanswered. Watanabe says the full mechanism is not yet understood, and other molecules likely play roles. He plans to investigate how microglia correctly interpret neuronal distress signals and why they respond to some cues but not others. Pepper is pursuing a related question: how often does skoupocytosis actually occur in healthy brains, and how important is it for normal synapse function? The team found the process happening in living tissue without artificially stimulating neurons, but in laboratory experiments, they could only reliably trigger organelle accumulation through artificial activity. This suggests skoupocytosis may be rare in undisturbed brains, occurring mainly when neurons are stressed or overworked. Understanding when and why neurons recruit this cleanup mechanism could eventually inform treatments for neurodegenerative diseases, where protein accumulation damages brain cells and contributes to cognitive decline.