Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration

• DOI: 10.1016/j.neuron.2025.02.007
• Publication Date: 2025-03-12T15:33:08Z
• Authors: Rocio Vicario; Stamatina Fragkog...; Maria Pokrovskii; Carina Meyer; Estibaliz Lopez-R...; Yang Hu; Masato Ogishi; Araitz Alberdi; Ann Baako; Oyku Ay; Isabelle Plu; Véronique Sazdovitch; Sebastien Heritier; Fleur Cohen-Aubart; Natalia Shor; Makoto Miyara; Florence Nguyen-Khac; Agnes Viale; Ahmed Idbaih; Zahir Amoura; Marc K. Rosenblum; Haochen Zhang; Elias-Ramzey Karnoub; Palash Sashittal; Akhil Jakatdar; Christine A. Iaco...; Omar Abdel-Wahab; Viviane Tabar; Nicholas D. Socci; Olivier Elemento; Eli L. Diamond; Bertrand Boisson; Jean-Laurent Casa...; Danielle Seilhean; Julien Haroche; Jean Donadieu; Frederic Geissmann

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations an increased risk of neurodegeneration. We found microglial mutant clones in LCH ECD patients, whether or not they presented clinical symptoms neurodegeneration, microgliosis, astrocytosis, neuronal loss, predominantly the rhombencephalon gray nuclei. Neurological were PU.1+ clone size (p = 0.0003) patients longest evolution disease, indicating a phase subclinical incipient Genetic barcoding analysis suggests that may originate from definitive yolk sac hematopoiesis, depending on patients. In mouse model, topography was attributable to local proliferative advantage, microglia depletion by CSF1R-inhibitor limited loss improved survival. These studies characterize neurodegenerative proliferation inflammatory microglia. The long preclinical stage represents therapeutic window before irreversible depletion.