A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

Abstract

Braf V600E expression in resident macrophage progenitors leads to clonal expansion of ERK-activated microglia, which causes synaptic and neuronal loss in the brain and results in lethal neurodegenerative disease in adult mice. Microglia—immune cells in the brain—derive from yolk-sac erythro-myeloid progenitors (EMPs), which are distinct from haematopoietic stem cells (HSCs). Frederic Geissmann and colleagues show that mosaic expression of a mutant BRAF, which activates the RAS–MEK–ERK pathway and causes tumours when expressed in HSCs, results in expansion of tissue-resident macrophages and late-onset neurodegeneration when expressed in EMPs. They show in a mouse model that neurobehavioural abnormalities, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death are driven by ERK-activated microglia and can be prevented by BRAF inhibition. These results show that, in mice, activation of the MAP kinase pathway in microglia can cause neurodegeneration. These findings may explain the neurodegeneration observed in patients with histiocytosis—disorders of myeloid cell expansion associated with somatic mutations in the RAS–MEK–ERK pathway, such as the BRAF mutation studied here. The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation1. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear1,2,3,4,5,6,7,8. Late-onset neurodegenerative disease observed in patients with histiocytoses9,10,11,12, which are clonal myeloid diseases associated with somatic mutations in the RAS–MEK–ERK pathway such as BRAF(V600E)13,14,15,16,17, suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease18,19. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells20,21,22,23. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, 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 that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.