Pathophysiology of microglial-driven neurodegeneration in Histiocytosis [Proj_11769]

L-Histiocytosis is a clonal myeloid disease characterized by BRAFV600E somatic mutations and increased risk of neurodegeneration, the mechanism of which is poorly understood. We report that microglia from histiocytosis patients is characterized by a high mutational load, dominated by the BRAFV600E variant. Genetic bar-coding analysis of the patients’ microglia, blood and/or bone marrow suggest that most microglia clones are generated or expanded locally. A diagnosis of neurodegeneration was linked to larger and more widespread clusters of mutant microglia. Microglial clones preferentially accumulate in the patients’ hippocampus and brainstem, attributable in part to a local proliferative advantage over time in mouse models. snRNAseq showed that BRAFV600E microglia cause neuro-inflammation, a neurotoxic astrocyte response, and preferential loss of pons glutamatergic and GABAergic neurons. Early treatment with CSF1R-inhibitor depleted mutant microglia, limited neuronal loss, improved symptoms, and prolonged survival in mice, suggesting that preventive treatment may alleviate neurodegeneration in Histiocytosis.