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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The somatic BRAF p.V600E variant in the microglial lineage has been causally implicated in degeneration of neurons secondary to clonal expansion and activation of mutant microglia in both mouse models and humans.
“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]
The paper’s Abstract reports that BRAFV600E-mutant microglia expand and drive neuronal loss in mice, with BRAF inhibition reducing the pathology. It also reports activated BRAFV600E-positive microglia at sites of neuronal loss in human histiocytosis patients, but describes the human findings as shared features rather than a demonstration of causation in humans. Page numbers are not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMicroglial proliferation and activation induced by a BRAF mutation restricted to erythromyeloid progenitors could drive late-onset neurodegeneration.
“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
Microglia from BRAF mutant mice and from brain tissue of patients with BRAF mutation-associated neurodegenerative disease showed increased inflammatory cytokine expression.
“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
Microglia proliferation preceded neuron loss in the BRAF mutant mice.
“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
Exacerbated activation of microglia promotes microglia-mediated neuronal attrition.
“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]
When the RAF-MEK-ERK pathway is activated cell-autonomously in microglia, synapses are lost and a severe late-onset neurodegenerative disorder develops.
“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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“Mass et al. investigated neurodegeneration that occurs in the context of neurohistiocytosis, as this disease can harbor BRAFV600E [7].”
BackgroundInfluentialThe coming of age of Langerhans cell histiocytosis
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“However, abnormally activated glial cells (Mass et al. 2017; Goldmann et al. 2013) and B lymphocytes (Mass et al.”
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BackgroundSomatic mutations in neurons during aging and neurodegeneration
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Fetal-Derived Immune Cells at the Roots of Lifelong Pathophysiology
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Self-citationCentral nervous system involvement in Erdheim-Chester disease
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“The limited efficacy of targeted therapies on CNS manifestations, compared to their dramatic effects in other localizations, has several potential explanations: a lower diffusion in CNS due to the blood–brain barrier; the nontumoral mechanism of pseudodegenerative lesions, in which no histiocytes are observed, leading…”
BackgroundSomatic Variants: New Kids on the Block in Human Immunogenetics
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Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction
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“For example, somatic mutations in the BRAF oncogene in erythro-myeloid precursors of microglia result in progressive neurological impairment with multiple features of cerebellar ataxia (7).”
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“…markers of inflammation and changes in immune cells in the autopsy pathology specimens of patients with various neurosystemic diseases, such as Parkinson ’ s Disease (PD), multiple sclerosis (MS), and stroke (Mass et al., 2017; Wang et al., 2023; Lambertsen et al., 2019; Tansey et al., 2022).”
BackgroundSpecialized functions of resident macrophages in brain and heart
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Mosaic loss of Chromosome Y in aged human microgliaPreprint
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Synapse Dysfunctions in Multiple Sclerosis
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“However, also abnormally activated glial cells [23,24] and B-lymphocytes play an important role [22,25–31].”
BackgroundMAP-Kinase-Driven Hematopoietic Neoplasms: A Decade of Progress in the Molecular AgePreprint
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Self-citationSomatic mutations in autoinflammatory and autoimmune disease
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Prenatal Origin of Pediatric Leukemia: Lessons From Hematopoietic Development
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The Microglial Response to Neurodegenerative Disease
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“For example, ERKactivated microglia were shown to drive astrogliosis, synaptic loss, neuronal death and neurobehavioral deficits in mice [32], while activation of the NF-κB signaling in microglia induced motor neuron loss in ALS [33].”
BackgroundAn update on the treatment of pediatric-onset Langerhans cell histiocytosis through pharmacotherapy
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“Geissmann sheds light on the underlying mechanism of the neurodegenerative CNS-LCH with possible therapeutic implications [48].”
BackgroundFrom macrophage biology to macrophage-based cellular immunotherapies
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Self-citationOne Size Does Not Fit All: Heterogeneity in Developmental Hematopoiesis
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A microglia clonal inflammatory disorder in Alzheimer’s disease
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“…associated with neurodegeneration ( Mass et al., 2017 ; Boyd et al., 2020 ; Bhatia et al., 2020 ; Diamond et al., 2016 ), and introduction in mouse microglia of the variant allele most frequently associated with histiocytosis (BRAF V600E ) causes neurodegeneration in mice ( Mass et al., 2017 ).”
InfluentialSelf-citationIDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation
Park, J. W., Kwak, J., Kim, K. W., Jung, S., Nam, C. H., Kim, H. J., Lee, S. M., Choi, C., Ahn, Y., Park, J., et al. (2026) · Science · doi:10.1126/science.adt0559 · Cited by 23 · see citing works
Tumorigenic Interplay Between Macrophages and Collagenous Matrix in the Tumor Microenvironment
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Allogenic microglia replacement: A novel therapeutic strategy for neurological disorders
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“Mass and colleagues demonstrated that the mosaic BRAF V600E mutation in microglia causes the clonal expansion of dysfunctional microglia, leading to the formation of astrogliosis, the deposition of A 𝛽 , loss of synapse, and a decline in cognitive function [117] .”
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“Our findings suggest that microglia dynamic alterations might represent a turning point in AD pathology progression, contributing to Aβ plaque formation, FSI dysfunction, and circuit failure in the hippocampus.”
Horebeek, L. V., Hilven, K., Mallants, K., van Nieuwenhuijze, A. E. M., Kelkka, T., Savola, P., Mustjoki, S. M., Schlenner, S., Liston, A., Dubois, B., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy425 · Cited by 17 · see citing works
“For some somatic variants, it may even be possible to target the affected pathway itself, as examples such as BRAF or STAT3 inhibitors for other autoimmune and neurological diseases illustrate (18,19).”
Advances in Genetic and Molecular Understanding of Alzheimer’s Disease
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“While no mutations have been found within the MAPK pathway that are associated with AD, somatic mutations in the BRAF gene (which is part of the MAPK pathway) in the erythro-myeloid progenitor lineage in mice may cause neurodegeneration [26].”
BackgroundRole of Microglia in Central Nervous System Development and PlasticityPreprint
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- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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