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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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Unraveling the enigma: housekeeping gene Ugt1a7c as a universal biomarker for microglia
Kim, W., Kim, M.-J., & Kim, B. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1364201 · Cited by 3
Cases‐Cunillera, S., Quatraccioni, A., Rossini, L., Ruffolo, G., Ono, T., Baulac, S., Auvin, S., O'Brien, T. J., Henshall, D. C., Akman, Ö., et al. (2024) · Epilepsia · doi:10.1111/epi.18126 · Cited by 2
Refractory Tumorous and Neurodegenerative Histiocytosis Treated With Intra-Arterial Chemotherapy
Ramos, A. D., Garton, A. L. A., Knopman, J., Bossert, D. F., Reiner, A. S., Nasany, R. A., Reilly, J. M., Padro‐Guzman, J., König, F., Abdel-Wahab, O. I., et al. (2025) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200495 · Cited by 2
“2 The precise etiology of ND-LCH remains unclear; however, it has been linked to a BRAFV600E-driven myeloid process, whether from tissue-resident 30 or hematopoietic cell origin, 31 with modest responses noted to BRAF inhibitor therapies.”
Self-citationLeducq Epigenetics of Atherosclerosis Network
de Winther, M. P. J., & Glass, C. K. (2019) · Circulation Research · doi:10.1161/circresaha.119.315187 · Cited by 2
“The group of Geissmann could show that a somatic mutation in BRAF strongly impacts on myeloid cell activation and thereby affects neuroinflammation in mice and human patients.(13) Relatively little is understood of the underlying mechanisms whereby CHIP contributes to CVD.”
BackgroundTailoring the immune response to the availability of nutrients
Cattenoz, P. B., & Giangrande, A. (2020) · FEBS Journal · doi:10.1111/febs.15304 · Cited by 2
Blank-Stein, N., Mayer, M., & Mass, E. (2021) · Advances in immunology · doi:10.1016/bs.ai.2021.08.001 · Cited by 2
Self-citationMacrophage self‐renewal is regulated by transient expression of PDGF‐ and VEGF‐related factor 2
Bakopoulos, D., Whisstock, J. C., Warr, C. G., & Johnson, T. K. (2022) · FEBS Journal · doi:10.1111/febs.16364 · Cited by 2
The Roots of Neurodegenerative Disease Found in Developmental Hematopoiesis
Milsom, M. D. (2017) · HemaSphere · doi:10.1097/hs9.0000000000000010 · Cited by 2
“In order to test this hypothesis in the mouse, Mass and colleagues used a tamoxifen-inducible Cre recombinase, driven by theCsf1 receptor locus, to delete LoxP-flanked stop cassettes upstream of Braf and Rosa26 alleles in yolk-sac erytho-myeloid progenitors.(1) Injection of pregnant female mice with 4-hydroxytamoxifen…”
BackgroundMethodA microglia clonal inflammatory disorder in Alzheimer’s DiseasePreprint
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B. P., Socci, N. D., Alberdi, A., Baako, A., et al. (2024) · eLife · doi:10.7554/elife.96519.2 · Cited by 2
Self-citationDeciphering Langerhans cell histiocytosis
Haroche, J., & Azoulay, L.-D. (2025) · Blood · doi:10.1182/blood.2024027473 · Cited by 2
A maelstrom of migrating monocytes drives neurodegeneration
Coufal, N. G., & Hermiston, M. L. (2023) · Immunity · doi:10.1016/j.immuni.2023.11.014 · Cited by 1
Neurodegeneration in Langerhans Cell Histiocytosis: beyond a Sequela
López, V. S., Gutiérrez-Carrasco, I., Pérez-Martínez, A., Iturrate, C. R.-V., García‐Obregón, S., Reggiori, M. L., Carrillo, T. M., Valero‐Arrese, L., Torrent, M., & Astigarraga, I. (2026) · Anales de Pediatría (English Edition) · doi:10.1016/j.anpede.2026.504058 · Cited by 1
Pathogenic myeloid phenotypes drive disease pathology in a novel human neurohistiocytosis model
Rajamanickam, S., Trescott, S., Mak, S., Warden, A. S., Wilpitz, A., Xia, B., Nguyen, C. T., Ding, H., Picarsic, J. L., Glass, C. K., et al. (2026) · Blood · doi:10.1182/blood.2025032207 · Cited by 1
How can cancer research be illuminated by brain research (and vice versa)?
Mentis, A. A., Papavassiliou, K. A., Piperi, C., & Papavassiliou, A. G. (2023) · International Journal of Cancer · doi:10.1002/ijc.34682 · Cited by 1
“Moving forward, the overexpression of the now well-known BRAF (V600E) mutations in murine erythron-myeloid progenitor cells, which are precursors to microglia cells, clarified their role as the fetal cellular origin for histiocytosis (ie, a spectrum of myeloid diseases) but also revealed broader mechanisms of microgli…”
BackgroundDaifu, T., Umeda, K., Yokoyama, A., Yoshida, T., Saida, S., Kato, I., Hiramatsu, H., Kudo, K., Higuchi, Y., & Takita, J. (2024) · Pediatric Blood & Cancer · doi:10.1002/pbc.31043 · Cited by 1
Altered cerebral perfusion in children with Langerhans cell histiocytosis after chemotherapy
Han, M., Kim, L. H., Shpanskaya, K. S., Kim, C., Iv, M., Jeng, M., & Yeom, K. W. (2019) · Pediatric Blood & Cancer · doi:10.1002/pbc.28104 · Cited by 1
Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNKPreprint
Ye, Q., Al-Kuwari, N., Srivast, P., & Chen, X. (2021) · Research Square · doi:10.21203/rs.3.rs-220057/v1 · Cited by 1
“Constitutive activation of BRAF by low-level expression of BRAFV600E in the mouse germline is associated with increased number of astrocytes with unaltered neuron number in hippocampal area [14].”
BackgroundBRAFV600E-induced senescence drives Langerhans Cell Histiocytosis pathophysiologyPreprint
Mérad, M. (2020) · doi:10.21203/rs.3.rs-98634/v1 · Cited by 1
“Recent studies in mice suggest that BRAFV600E expression in murine embryonic erythromyeloid-progenitor (EMP) can lead to a neurodegenerative in ammatory disorder without systemic involvement (Mass et al., 2017), although this is rarely the case in patients where LCH-ND arises more”
BackgroundThreshold of somatic mosaicism disrupting the brain functionPreprint
Kim, J., Park, S. M., Koh, H. Y., Ko, A., Kang, H., Chang, W. S., Kim, D. S., & Lee, J. H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.30.573716 · Cited by 1
A microglia clonal inflammatory disorder in Alzheimer’s DiseasePreprint
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B. P., Socci, N. D., Alberdi, A., Baako, A., et al. (2024) · eLife · doi:10.7554/elife.96519.1 · Cited by 1
Self-citationMosaicism of BRAF(V600E) in Healthy Skin Predicts Neurodegeneration in HistiocytosisPreprint
Emile, J., Hélias‐Rodzewicz, Z., Papo, M., Ungureanu, I. A., Baek, C., Triboulet, F., Wong, T. H., Jannet, R. B., Terrones, N., Es-Qalli, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.17.688335 · Cited by 1
Papers of note in Nature 549 (7672)
VanHook, A. M. (2017) · Science Signaling · doi:10.1126/scisignal.aaq0242
European Molecular Biology Organization (EMBO) Workshop: Microglia 2018
Horiuchi, H. (2018) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12468
“As a new hypothesis, Dr Mass suggested that neurodegenerative diseases seen in leukemic and tumoral diseases caused by somatic BRAF (V600E) mutation in erythro-myeloid progenitors is of microglial origin.(16) According to his report, BRAF (V600E) mutation in the erythro-myeloid progenitors caused a severe late-onset n…”
BackgroundImmune Mechanisms in Arterial Homeostasis and Disease
Besla, R. (2019) · TSpace (University of Toronto)
Single-Cell RNA Sequencing Reveals a Developmental Hierarchy in Langerhans Cell Histiocytosis
Gruber, T. A. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0820
“Consistent with this hypothesis, a recent study introducing BRAFV600E into yolk sac erythromyeloid progenitors (EMP) of mice led to clonal expansion of tissue-resident macrophages followed by late-onset neurodegenerative disorder, a complication of LCH that occurs in a small subset of patients (6).”
ResultKoch, B. M. E. (2019) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7716
“This early mutation within the myeloid cell lineage resulted in the lateonset development of neurodegeneration and therefore further supports the idea of microglia as contributors on AD development (Mass et al., 2017).”
ResultExtrapulmonary Manifestations of Diffuse Cystic Lung Diseases
Dilling, D. F., & Ruoss, S. J. (2021) · Respiratory medicine · doi:10.1007/978-3-030-63365-3_15
Beggs, S. (2021) · Oxford University Press eBooks · doi:10.1093/med/9780198818762.003.0007
Metabotropic Glutamate Receptor 5 Negative Allosteric Modulation Effects on Microglia Phenotype
Curtis, N. (2021) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2021-14640
“…shows that excessive M1 polarization of the microglia can lead to exacerbation of injury and progressive tissue destruction, otherwise known as the M1 neurotoxic phenotype which is associated with virtually all neurodegenerative diseases (Hoshi et al., 2019; Loane et al., 2014; Mass et al., 2017).”
BackgroundMoriuchi, Y. W., Iwagawa, T., Tsuhako, A., Koso, H., Fujita, Y., & Watanabe, S. (2020) · doi:10.21203/rs.3.rs-29744/v1
“A recent study showed that microglial expression of a constitutively active form of BRAF, BRAFV600E, promoted microglia expansion and late-onset neurodegeneration in the brain [16].”
BackgroundBasturea, G. N. (2018) · Materials and Methods · doi:10.13070/mm.en.8.2673 · Cited by 2
Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNKPreprint
Ye, Q., Al-Kuwari, N., Srivast, P., & Chen, X. (2021) · Research Square · doi:10.21203/rs.3.rs-220057/v2
Chiang, V. S., Lipkin, S., McCusker, C., & Park, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.08.519640
“Anti-Iba1 was validated using mouse retinal whole-mount and cited in an erythro-myeloid progenitors study (Mass et al., 2017).”
MethodEmbryonic lymphocytes contribute to a genetic form of autoimmune inflammationPreprint
Cascione, S., Fontana, E., Scarfò, R., Rigoni, R., Capo, V., Draghici, E., Dobbs, K., Notarangelo, L. D., VILLA, A. M., & Ditadi, A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.24.568475
Pizzirusso, G., Preka, E., Goikolea, J., Aguilar-Ruiz, C., Rodriguez‐Rodriguez, P., Cabrera, G. V., Laterza, S., Latorre‐Leal, M., Eroli, F., Blomgren, K., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.14.584993
Yue, W., Deng, X., Wang, Z., Jiang, M., Hu, R., Duan, Y., Wang, Q., Cui, J., & Fang, Y. (2023) · Figshare · doi:10.6084/m9.figshare.23550334
Infusion of blood from young and old mice modulates amyloid pathology
Pizarro, M., Gomez‐Gutierrez, R., Caviedes, A., Valdes, C., Woehlbier, U., Vargas, C., Hernández, M., Duran-Aniotz, C. A., & Morales, R. (2025) · Aging · doi:10.18632/aging.206319
“The dysregulation of this protein has been linked with neurodegenerative processes, including tau hyperphosphorylation and neuronal dysfunction in AD [82, 83], as well as microglial proliferation and neuroinflammation [84, 85].”
Megeed, R. M. A., Kadry, M. O., Abdel‐Hamid, A. Z., Afifi, S. M., & Ammar, N. M. (2025) · OpenNano · doi:10.1016/j.onano.2025.100261
Neurodegeneración en histiocitosis de células de Langerhans: más que una secuela
López, V. S., Gutiérrez-Carrasco, I., Pérez‐Martínez, A., Iturrate, C. R.-V., García‐Obregón, S., Reggiori, M. L., Murciano, T., Valero‐Arrese, L., Torrent, M., & Astigarraga, I. (2025) · Anales de Pediatría · doi:10.1016/j.anpedi.2025.504058
Yue, W., Deng, X., Wang, Z., Jiang, M., Hu, R., Duan, Y., Wang, Q., Cui, J., & Fang, Y. (2023) · Figshare · doi:10.6084/m9.figshare.23550331
Louadi, Z., Elkjaer, M. L., Klug, M., Lio, C. T., Fenn, A. M., Illés, Z., Bongiovanni, D., Baumbach, J., Kacprowski, T., List, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.17120378
Louadi, Z., Elkjaer, M. L., Klug, M., Lio, C. T., Fenn, A. M., Illés, Z., Bongiovanni, D., Baumbach, J., Kacprowski, T., List, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.17120420
Pleuropulmonary Erdheim-Chester Disease
Tessier, S., Go, R. S., & Ryu, J. H. (2026) · Springer eBooks · doi:10.1007/978-3-032-14873-5_24
Bigenwald, C. (2019) · theses.fr (ABES) · doi:10.70675/50d69840zbc47z441dzaae6ze3dfe561b1dd
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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