Proximity Labelling Reveals the Compartmental Proteome of Murine Sensory Neurons

ABSTRACT Introduction Understanding the molecular architecture of peripheral sensory neurons is critical as we pursue novel drug targets against pain and neuropathy. Sensory neurons in the dorsal root ganglion (DRG) show extensive compartmentalization; thus, understanding each compartment—from the peripheral to central terminals—is key to this effort. Methods To systematically profile this spatial complexity, we generated a TurboID fl/fl transgenic mouse line (ROSA26 em1(TurboID)Bros ), enabling targeted proximity labelling and deep proteomic profiling of DRG neuron compartments via Tg(Advillin‐Cre) + . Results Our data reveal distinct proteomic signatures across neuronal compartments that reflect specialized neuronal functions. We provide proteomic insights into previously inaccessible nerve terminals both in the periphery (innervating the skin) and in the spinal cord. Further, using a DRG explant model of chemotherapy‐induced peripheral neuropathy, we uncover novel and discrete proteome changes, highlighting neuronal vulnerability. Conclusion Together, our findings provide a unique proteome atlas of the sensory neuron proteome across anatomical domains and demonstrate the utility of proximity labelling proteomics for detecting compartment‐specific molecular alterations in a disease model. Significance This study highlights the potential of TurboID‐based proteomics to uncover cell type‐specific differences in the peripheral nervous system, serving as a valuable resource for mechanistic studies of sensory neuron function and pathology.