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A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease
Open accessAbstract
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.
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In the citing paper
“Moreover, the somatic BRAF p.V600E variant, a common cancer driver variant, in the microglial lineage has been causally implicated not in cancer, but instead in degeneration of neurons secondary to clonal expansion and activation of mutant microglia in both mouse models and humans29.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [29]
Experimental — accuracy not yet measuredIn the citing paper
“a recent study using transgenic mice showed that microglial proliferation and activation induced by a BRAF mutation restricted to erythromyeloid progenitors could drive late-onset neurodegeneration (Mass et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Mass et al., 2017
In the citing paper
“microglia from the mutant mice as well as from brain tissue of patients with BRAF mutation–associated neurodegenerative disease showed increased inflammatory cytokine expression (Mass et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Mass et al., 2017
In the citing paper
“Importantly, microglia proliferation preceded neuron loss, and microglia from the mutant mice as well as from brain tissue of patients with BRAF mutation–associated neurodegenerative disease showed increased inflammatory cytokine expression (Mass et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Mass et al., 2017
In the citing paper
“Exacerbated activation of microglia has been shown to promote microglia-mediated neuronal attrition7,8.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [7]
In the citing paper
“The ability of aberrant intrinsically activated microglia to cause neuronal damage is further supported by recent findings showing that cell-autonomous activation of the RAF–MEK–ERK pathway in microglia leads to the loss of synapses and the development of a severe late-onset neurodegenerative disorder7.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [7]
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Microglia in Alzheimer’s disease
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Metadata
- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Freiburg (DE)
- ORCID
- Venue
- Nature
- Published
- 2017-08-30
- Volume
- 549
- Issue
- 7672
- Pages
- 389-393
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6047345
- OpenAlex
- W2750719748
- Cited by
- 210
- References
- 41
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 29 · 2023: 18 · 2022: 12 · 2021: 27 · 2020: 27 · 2019: 29 · 2018: 26 · 2017: 7
- FWCI
- 12.07
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL138090)
- National Cancer Institute (R01CA201247, P30CA008748)
- National Institute of Allergy and Infectious Diseases (R01AI130345)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- neurodegeneration, microglia, erythro-myeloid progenitors, BRAF V600E mutation, Ras/MEK/ERK pathway, histiocytosis, clonal expansion, MAPK signaling, astrocyte activation, amyloid precursor protein, synaptic loss, neuronal cell death, BRAF inhibition, yolk sac, tissue-resident macrophages, glial activation
- MeSH terms
- Animals, Clone Cells, Disease Models, Animal, Female, Humans, Macrophages, Male, Mosaicism, Mutation, Histiocytosis, Erythroid Precursor Cells, Microglia, Neurodegenerative Diseases, MAP Kinase Signaling System, Myeloid Progenitor Cells, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mice
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