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Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration

ABSTRACT: Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and increased risk of late-onset neurodegeneration. Surprisingly, we found microglia mutant clones associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the grey nuclei of the rhombencephalon, in patients with LCH and ECD whether or not they presented with clinical symptoms of neurodegeneration at the time of death. The presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003), indicating a phase of subclinical incipient neurodegeneration. Depletion of mutant microglia by a CSF1R-inhibitor in a mouse model of incipient disease limited neuronal loss and improved survival. Disease topography was attributable to a local proliferative advantage of mutant microglia. Genetic bar-coding analysis suggest that mutant clones originate from either definitive or yolk sac hematopoiesis depending on patients. These studies characterize a progressive neurodegenerative disease associated with clonal proliferation of inflammatory microglia (CPIM), and a preclinical stage of incipient disease which represents a therapeutic window for prevention of neuronal death.

ORGANISM(S): Mus musculus

PROVIDER: GSE288761 | 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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Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration

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