Wu Jieyu, Yarmey Victoria R, Yang Olivia Jiaming, Soderblom Erik J, San-Miguel Adriana, Yan Dong
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Joint Department of Biomedical Engineering, North Carolina State University, University of North Carolina at Chapel Hill, Raleigh, NC, USA.
Nat Neurosci. 2025 Jun 18. doi: 10.1038/s41593-025-01989-0.
The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted signals through ligand-receptor interactions on the cell membrane. Here we show a new mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ of Caenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the cross-talk between neurons and glia. We demonstrate that early aged neurons can transmit heat shock proteins to glia via extracellular vesicles. These neuronal heat shock proteins activate the glial IRE1-XBP1 pathway, leading to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a new mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.
神经系统主要由神经元和神经胶质细胞组成，它们之间的通讯在调节大脑的发育和功能方面具有深远作用。已知神经元与神经胶质细胞之间的信号转导是通过分泌信号在细胞膜上的配体 - 受体相互作用介导的。在此，我们展示了一种神经元 - 神经胶质细胞信号转导的新机制，即神经元通过细胞外囊泡将蛋白质传递给神经胶质细胞，激活神经胶质细胞的信号通路。我们发现，在秀丽隐杆线虫的两性感觉器官中，不同的感觉神经元表现出不同的衰老速率。这种衰老差异受神经元与神经胶质细胞之间的相互作用调控。我们证明，早衰的神经元可以通过细胞外囊泡将热休克蛋白传递给神经胶质细胞。这些神经元热休克蛋白激活神经胶质细胞的IRE1 - XBP1通路，导致硫酸软骨素合成酶的转录调控，以保护嵌入神经胶质细胞的神经元免受与衰老相关的功能衰退。因此，我们的研究揭示了神经系统中神经元 - 神经胶质细胞通讯的新机制，并为我们理解大脑衰老提供了新的见解。
