The nervous system is a complex network of neurons that coordinate the body by transmission of electrical signals. And just like the power lines that deliver electricity to homes and businesses, the nervous system sometimes needs maintenance.
During early development, animals are constantly eliminating unnecessary neuronal material; the nervous systems of insects that undergo metamorphosis are altered as they transition. Physical injury in all stages of life can also cause nerve damage.
In all cases, the unneeded or damaged neurites must be eliminated for the body to maintain tissue equilibrium. But what if a removal signal is erroneously sent out, and the healthy neuronal material is targeted for removal? Could this lead to neurodegenerative disease?
The lab of Chun Han, assistant professor of molecular biology and genetics, investigated those questions by seeing what would happen if a healthy neurite sent out the cleanup – or “eat-me” – signal. The answers might pave the way to deeper understanding of the Neurodegenerative disease. The group’s paper, “Phosphatidylserine Externalization Results From and Causes Neurite Degeneration in Drosophila,” published in the journal Cell Reports. The lead authors are Maria Sapar and Hui Ji, both doctoral students and members of the Han Lab.
When cells are no longer useful and die through a process known as apoptosis, they expose on their surface a phospholipid molecule called phosphatidylserine (PS), which acts as an “eat-me” signal so that phagocytes – cells that specialize in cleaning garbage in the body – know to clear out the dead cells.
Recent studies suggest PS may play the same role in neurite degeneration, so Han and his team – with chemicals provided by the Gene Regulatory Lab at Tsinghua University of Beijing, China – tested that theory on both larval and adult Drosophila (fruit flies).
They first developed fluorescent probes to detect PS exposed on the surface of neurons in live Drosophila larvae. Indeed, dendrites that were cut off from the cell body by lasers or trimmed off during metamorphosis exposed PS in waves before dendrites fragmented. However, when the researchers genetically blocked the degeneration of the detached dendrites, PS exposure was never detected.
“When the dendrite or the neuron degenerates, it exposes PS, but we wondered: Is this just coincidence?” Han said. “Are we just seeing them at the same time, or is PS important in helping to cause interaction with the phagocytes?”
PS is controlled by two proteins, both of which cause the movement of phospholipid molecules between the cell membrane’s two leaflets. The “flippase” protein is responsible for flipping PS into the cell, while the “scramblase” is responsible for exposing PS onto the outer leaflet.
Han’s group simultaneously knocked out the flippase and overexpressed the scramblase in Drosophila larvae, resulting in heightened PS exposure – the “eat-me” signal. Time-lapse imaging showed healthy dendrites – the branches of the neuron “tree” – being consumed by nearby epidermal cells acting as phagocytes.
“We found that when we caused the neurons to expose PS, they lost their dendrite membrane,” Han said. “They shed membrane off from the tip and sometimes from the shaft of the dendrite. … The nearby epithelial cells, which normally support them, now become phagocytes. They recognize the PS and attack these dendrites.”
The group next tested the theory on the central nervous system of adult Drosophila, but with a twist: Olfactory neurons in the antenna respond to odors, particularly fruit odors, and when this happens, channels open up and allow entry of calcium into the neuron.
Calcium activates the scramblase, which in turn exposes the PS, which in turn sends the “eat-me” signal to nearby phagocytes, which attack the nerve fibers. The group tested flies with and without the odor stimulation, and there was “a huge difference” in the level of neurite degeneration, Han said, with the odor-exposed flies experiencing far more neurite loss.
“When you activate these neurons, it turns on the scramblase and really causes a high level of PS exposure on the surface,” Han said. “That likely attracts nearby phagocytes to attack the neurons.”
It’s possible, Han said, that early symptoms of the Neurodegenerative disease could be caused by loss of neurites due to faulty signaling, perhaps caused by genetic mutation of the flippase or scramblase phospholipids.
“If there was a way to correct this genetic defect,” he said, “and boost the function of the flippase, maybe that could prevent the occurrence of neurodegenerative disease.”
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