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. Analysis of BRAFVE and WT microglia from cortex and brainstem from 2 months and end-stage mice