Wu Ling, Pandey Vijaya, Casha Vanessa H, Qu Zhe, Jami-Alahmadi Yasaman, Gradinaru Viviana, Wohlschlegel James A, Khakh Baljit S
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
Neuron. 2025 Jun 5. doi: 10.1016/j.neuron.2025.05.019.
Neurons and astrocytes are predominant brain cells that extensively interact, but the molecular basis of their interactions remains largely unexplored. We identified and mapped striatal astrocytic and neuronal cell-surface proteins (CSPs) and found that many were shared, representing the cell-surface shared proteome of astrocytes and neurons (CS SPAN) bridging striatal astrocyte-neuron interaction sites. CS SPAN was replete with extracellular matrix proteins, cell adhesion molecules, transporters, ion channels, and G protein-coupled receptors. By mapping the cellular origins of astrocytic CSPs, we identified astrocytic interactions with diverse parenchymal cells. Broadly concordant with human data, in a mouse model of Huntington's disease (HD), pathophysiology and its genetic attenuation were accompanied by altered and restored CS SPAN and CSPs, respectively. CS SPAN also included molecules dysregulated in diverse brain disorders. Our study reveals the astrocyte-neuron interface in molecular terms and provides a mechanistic foundation for exploring its physiological roles and contributions to brain diseases.
神经元和星形胶质细胞是广泛相互作用的主要脑细胞，但它们相互作用的分子基础在很大程度上仍未被探索。我们鉴定并绘制了纹状体星形胶质细胞和神经元细胞表面蛋白（CSP）图谱，发现许多蛋白是共享的，代表了连接纹状体星形胶质细胞 - 神经元相互作用位点的星形胶质细胞和神经元的细胞表面共享蛋白质组（CS SPAN）。CS SPAN富含细胞外基质蛋白、细胞粘附分子、转运蛋白、离子通道和G蛋白偶联受体。通过绘制星形胶质细胞CSP的细胞起源图谱，我们确定了星形胶质细胞与多种实质细胞的相互作用。与人类数据大致一致，在亨廷顿舞蹈病（HD）小鼠模型中，病理生理学及其基因减弱分别伴随着CS SPAN和CSP的改变和恢复。CS SPAN还包括在多种脑部疾病中失调的分子。我们的研究从分子层面揭示了星形胶质细胞 - 神经元界面，并为探索其生理作用及对脑部疾病的贡献提供了机制基础。
