A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

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 activation(1). Whether microglial activation, which is viewed in general as a secondary process, is detrimental or protective in neurodegeneration remains unclear(1–8). Late-onset neurodegenerative disease observed in patients with histiocytoses(9–12), which are clonal myeloid diseases associated with somatic mutations in the RAS/MEK/ERK pathway such as BRAF(V600E 13–17), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet expression of BRAF(V600E) in the hematopoietic stem cell (HSC) lineage causes leukemic and tumoral diseases but not neurodegenerative disease(18,19). Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk sac erythro-myeloid progenitors (EMP) distinct from HSC(20–23). We thus hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in EMP results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder, associated with accumulation of ERK-activated amoeboid microglia in mice, also observed in human histiocytoses patients. In the murine model, neurobehavioral signs, astrogliosis, amyloid precursor protein deposition, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses, and demonstrate in mice 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 neurodegeneration, and provide opportunities for therapeutic intervention aimed at preventing neuronal death in neurodegenerative diseases.