A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease Journal Article


Authors: Mass, E.; Jacome-Galarza, C. E.; Blank, T.; Lazarov, T.; Durham, B. H.; Ozkaya, N.; Pastore, A.; Schwabenland, M.; Chung, Y. R.; Rosenblum, M. K.; Prinz, M.; Abdel-Wahab, O.; Geissmann, F.
Article Title: A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease
Abstract: 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 activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), 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 disease. 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 cells. 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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Keywords: mitogen activated protein kinase; controlled study; somatic mutation; mutation; nonhuman; pathophysiology; flow cytometry; mouse; mus; gene expression; bone marrow; animal experiment; animal model; caspase 3; immunofluorescence; central nervous system; physiology; histone h3; kupffer cell; hematopoietic stem cell; macrophage; cell suspension; neurologic disease; myeloid progenitor cell; degenerative disease; cell selection; amyloid precursor protein; rna sequence; nerve degeneration; disease; microglia; rotarod test; cells and cell components; nervous system disorder; human; priority journal; article
Journal Title: Nature
Volume: 549
Issue: 7672
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2017-09-21
Start Page: 389
End Page: 393
Language: English
DOI: 10.1038/nature23672
PROVIDER: scopus
PUBMED: 28854169
PMCID: PMC6047345
DOI/URL:
Notes: Article -- Export Date: 4 December 2017 -- Source: Scopus
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MSK Authors
  1. Marc Rosenblum
    249 Rosenblum
  2. Young Rock Chung
    46 Chung
  3. Benjamin Heath Durham
    60 Durham
  4. Neval   Ozkaya
    18 Ozkaya
  5. Alessandro   Pastore
    22 Pastore
  6. Elvira   Mass
    6 Mass