Trimming neuronal axons involves a distinct pathway and a rare pathogen-sensing immune protein that could have implications for Alzheimer鈥檚 disease.
Neurons have the remarkable ability to kill parts of themselves without dying in a phenomenon known as axon pruning. During axon pruning, neurons trim unnecessary axons, long, threadlike projections from nerve cells that transmit electrical signals to other cells.
鈥淎xon pruning fine tunes the connectivity and communications between neurons. Just think about the preciseness with which this system must consolidate one axon but not the other,鈥� said , a professor in the Department of Cell Biology and Physiology and the Neuroscience Center at the University of North Carolina at Chapel Hill.
In an , Selena Romero, a scientist in Deshmukh鈥檚 lab who recently defended her PhD, found that axon pruning shares much of the same molecular degeneration machinery as apoptosis, a programmed mechanism by which cells die. However, Romero found that there are distinct differences. In particular, axon pruning requires the unexpected use of an immune molecule called NLRP1 typically activated during pathogen infection.
鈥淚t didn鈥檛 make sense for the neuron to express this because our axon pruning model doesn鈥檛 use viruses or any inflammatory stimulus,鈥� said Romero. Unlike apoptosis, axon pruning does not require the apoptosome complex to initiate degeneration. This suggested to Romero and Deshmukh, that axon pruning may occur through a different pathway.
鈥淲e started looking for other mechanisms cells use to activate caspases [the enzymes needed for degeneration] that are independent of the apoptosome,鈥� said Romero. They came across the inflammasome complex, which typically activates during immune responses.
She systematically knocked out the expression of the essential components involved in the inflammasome complex one at a time until finally, she found the lynchpin protein. When she removed NLRP1 expression, axon pruning did not occur.
How an immune protein got a new job in the brain
鈥淣LRP1 belongs to a family of pathogen sensing proteins. This one is an outlier and very few pathogens can activate it. It鈥檚 not the most well studied,鈥� said Deshmukh. NLRP1 activates in response to infections with anthrax and several viruses. It is also not a neuroimmune protein that typically interacts with the developing nervous system. 鈥淔rom our perspective, that is even more unexpected in that it is a bonafide immune molecule. What the heck is it doing in neurons in a nonpathogenic or diseased setting,鈥� said Deshmukh.
Romero reasoned that one advantage of utilizing the pathogen-sensing molecule NLRP1 for physiological axon pruning is that it may have evolved to quarantine potentially problematic axons to protect the body. If a virus infects distal axons in someone鈥檚 fingertips, for example, the virus could retroactively travel through the spine and affect the central nervous system. Thus, NLRP1 may not only regulate physiological axon pruning but could also halt the spread of pathogens in the nervous system.
鈥淭he other thing is that we have far fewer proteins in our genome than we thought we did,鈥� said Deshmukh. When researchers started sequencing the human genome, they thought humans had 50,000 to 100,000 genes. Now, they know humans have only 20,000 protein-coding genes, just 1,000 more than the roundworm C. elegans. 鈥淲e鈥檙e going to use the same proteins for multiple functions. NLRP1 has one ability to detect a pathogen and cause degradation. Why not engage the same protein under physiological conditions,鈥� said Deshmukh.
A potential therapeutic role in disease
NLRP1 may also have an unexpected role in Alzheimer鈥檚 disease. Another group noted that loss of NLRP1 expression in neurons improved Alzheimer鈥檚 disease outcomes in animal models. 鈥淣ow that we鈥檝e discovered the axon pruning function of NLRP1, it could very well be the case that there is unexpected hyperactivation of NLRP1 in Alzheimer鈥檚 disease, and inhibiting it could be a good therapeutic target,鈥� said Deshmukh.
Romero and Deshmukh鈥檚 findings show unequivocally that although apoptosis and axon pruning share many of the same molecular degradation events, they are two distinct pathways. Now they are on the quest to better understand those pathways and their roles in human health and disease.
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Romero, SE., Geden, MJ., Basundra, R., et al. . EMBO Reports 26(7), 1724-1736 (2025).
Written by Tiffany Garbutt, PhD