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Pathophysiology of microglial-driven neurodegeneration in Histiocytosis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273766 | GEO | 2025/04/15

REPOSITORIES: GEO

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Project description:The pathophysiology of neurodegenerative diseases is poorly understood, and therapeutic options are few. Neurodegenerative diseases are hallmarked by progressive neuronal dysfunction and loss, associated with chronic glial and immune activation1. Microglia are the resident macrophages of the nervous system thought to be important for the clearance of debris after neuronal damage and aid to repair and regeneration. Their activation is viewed in general as a reactive process in neurodegeneration1-3. Whether microglia itself may be causative of neurodegenerative diseases is unclear. Late-onset neurodegenerative disease is frequently observed in patients with histiocytoses4-10, which are clonal myeloid diseases associated with somatic mutations in the RAS/MEK/ERK pathway such as BRAFV600E 5,11,12, suggesting a possible role of somatic mutations in neurodegeneration. Yet, expression of BRAFV600E in the hematopoietic stem cell (HSC) lineage does not cause neurodegeneration13,14. However, recent works from our laboratories and other have revealed that microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk sac erythro-myeloid progenitors (EMP) distinct from HSC15-18. We thus hypothesized that somatic BRAFV600E mutations in the resident macrophage lineage may cause neurodegeneration. We found that while BRAFV600E expression in the HSC lineage causes leukemic and tumoral diseases13,14, its expression in the EMP lineage instead results in a severe late-onset neurodegenerative disorder. Neurological symptoms, neuronal death, astrogliosis, immune activation, and amyloid precursor protein deposition were driven by ERK-activated microglia clones and preventable by RAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses, and demonstrate that a somatic mutation in the EMP lineage can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegenerative disease, and provide opportunities for therapeutic intervention aimed at preventing neuronal death in neurodegenerative diseases

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Pathophysiology of microglial-driven neurodegeneration in Histiocytosis

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