From historical discovery to modern insight: Nageotte nodules in diabetic neuropathy

Aims: The study aimed to investigate the molecular identity of Nageotte nodules and their relevance to diabetic peripheral neuropathy (DPN). This investigation follows the initial discovery of these nodules in 1922 by Jean Nageotte, who described clusters of satellite glia replacing decomposed sensory neurons.

Methods: To achieve this, the researchers applied cutting-edge techniques to analyze dorsal root ganglia (DRG) collected from 90 organ donors with short post-mortem intervals, grouped based on their medical history of diabetes and DPN. Confocal imaging, spatial transcriptomics, immunohistochemistry, RNAscope in situ hybridization, and transmission electron microscopy were used to identify cellular components of Nageotte nodules and assess axonal changes. Ligand-receptor interactions were also explored to understand cellular communication and potential impacts on DPN pathology.

Results: Nageotte nodules were prevalent in DRGs of diabetic donors, particularly those with DPN, and were linked to sensory neuron loss and axonal dysfunction. Immunostaining revealed that Nageotte nodules were composed of non-myelinating Schwann cells and satellite glia, interleaved with neuroma-like axon bundles. Spatial transcriptomics showed that these structures express secreted ligands like osteopontin, which might interact with neuronal receptors and influence axonal sprouting. Additionally, surviving sensory neurons in DPN DRGs exhibited morphological changes, including axonal sprouting and loss of pseudounipolar form.

Conclusions: The findings indicate that Nageotte nodules play a significant role in DRG neurodegeneration in DPN, accompanied by extensive sensory neuron loss and aberrant axonal activity. These nodules potentially influence sensory neuronal activation and sprouting through ligand-receptor interactions. The study suggests that targeting these interactions might unlock therapeutic approaches for diabetes-induced neuropathic pain.

Comments: This research reveals that the structures first described by Jean Nageotte are not merely pathological artifacts but potentially key to understanding DPN mechanisms. The presence of Nageotte nodules correlates with significant DRG neurodegeneration and painful neuropathic features, highlighting the need for novel therapeutic strategies focusing on glial-neuronal interactions in DPN. By bridging historical observations with modern methodologies, the study underscores a comprehensive approach to determine underlying mechanisms of DPN and paves the way for targeted interventions against sensory neuron degeneration. Future research should aim to clarify the signalling pathways and cellular interactions involved in the formation and function of Nageotte nodules. Developing specialized animal models and advanced 3D culture systems will be vital for observing real-time changes and testing interventions over longer timescales. Clinical trials should focus on evaluating the diagnostic value of Nageotte nodules as biomarkers for neuropathic progression and response to treatment. Additionally, exploring similar mechanisms in other neuropathies or neurodegenerative diseases might extend the application of these findings to broader neurological contexts.

Stéphanie Eid

Reference: Shiers SI, Mazhar K, Wangzhou A, Haberberger R, Lesnak JB, Ezeji NA, Sankaranarayanan I, Tavares-Ferreira D, Cervantes A, Funk G, Horton P, Vines E, Dussor G, Price TJ. Nageotte nodules in human dorsal root ganglia reveal neurodegeneration in diabetic peripheral neuropathy. Nat Commun. 2025 May 5;16(1):4168. doi: 10.1038/s41467-025-59538-z. PMID: 40325011; PMCID: PMC12052976.

🔗 https://www.nature.com/articles/s41467-025-59538-z