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.
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We thank J. Donadieu and the Histiocytosis Study Group (Paris, France) for discussions during the course of this project, and C. Pritchard (University of Leicester, UK) for the Braf LSL-V600E strain and J. Pollard, (University of Edinburgh, UK) for Csf1r MerCreMer strain, Plexxikon Inc. for the gift of PLX-4720-impregnated and control chow, the Molecular Cytology Facility at MSKCC for tissue processing and histological staining. We acknowledge the use of the Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. This work was supported by National Cancer Institute of the US National Institutes of Health (P30CA008748) MSKCC core grant and grants from the Artemis Association/Histio (UK)/A.G. Leventis Foundation, Ludwig Institute for Cancer Research and NIH/NIAID 1R01AI130345-01 to F.G. E.M. was supported by an EMBO long-term Fellowship (ALTF 530-2015). A.P. is a Mildred-Scheel Postdoctoral Research Fellow of the Deutsche Krebshilfe e.V. (number 111354). B.H.D. is supported by the American Society of Hematology Research Training Award for Fellows. O.A.-W. is supported by grants from the Histiocytosis Association, the Erdheim-Chester Disease Global Alliance, the Pershing Square Sohn Cancer Foundation, a Leuekmia and Lymphoma Society Scholar award and NIH/NCI R01 CA201247-01. M.P. is supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the Sobek-Foundation, the DFG (SFB 992, SFB1140, SFB/TRR167, Reinhart-Koselleck-Grant) and the Ministry of Science, Research and Arts, Baden-Wuerttemberg (Sonderlinie “Neuroinflammation”).
The authors declare no competing financial interests.
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Extended data figures and tables
Extended Data Figure 1 Analysis of one-month-old Csf1r MeriCreMer;Braf LSL-V600E;Rosa26 LSL-YFP mice.
a, The percentage of mice born from the cross depicted in Fig. 1a according to their genotype (n = 42), but without injection of hydroxy-tamoxifen (4-OHT) to test for adverse effects of 4-OHT administration. b, Flow cytometry analysis of YFP expression in blood leukocytes. Representative of n = 8 mice per genotype. c, Flow cytometry analysis of YFP+ cells in the liver. YFP+ cells, present only in Csf1r MeriCreMer+ (Cre+) mice (top), were gated as F4/80+CD11b+ Kupffer cells (bottom). Representative of n = 8 mice per genotype. d, YFP expression by immunofluorescence in the liver of Braf VE and Braf WT mice. YFP+ cells are F4/80+ Kupffer cells. Representative of n = 6 mice per genotype. Scale bars, 200 μm and 5 μm (insets). e, Total tissue-resident macrophage cell numbers per gram (g) of tissue were analysed by flow cytometry in Braf VE mice (n = 4) and Braf WT (n = 6). Circles represent individual mice. Unpaired two-tailed t-test. f, In situ analysis of phospho-histone H3 (pHis3) staining in YFP+ cells from brains of Braf VE and Braf WT mice. Circles represent individual mice (n = 3). Unpaired two-tailed t-test. g, RNA-seq analysis, heatmap of MAPK target genes in YFP+ microglia from Braf VE (n = 3) and Braf WT (n = 2) mice, values are displayed as z scores. h, Histological analysis of liver, lung, kidney and spleen in Braf VE and Braf WT mice. HE, haematoxylin and eosin. Representative of n = 4 mice per genotype. Scale bars, 200 μm and 10 μm (insets).
Extended Data Figure 2 Effect of constitutive Braf V600E expression in Csf1r-expressing cells.
a, Breeding scheme. b, Embryonic lethality of Csf1r iCre+;Braf LSL-V600E;Rosa26LSL-YFP mice, bars represent the percentage of mice born from the cross depicted in a according to their genotype (n = 39). c, Bright field (top) and epifluorescence microscopy (bottom) of Csf1r iCre+Braf VE and Csf1r iCre+;Braf WT embryos showing haemorrhagic foci in the liver (arrow) and accumulation of YFP+ cells in the fetal liver. A dead embryo is indicated by a dagger (†). Pictures are representative of n = 3 per genotype. d, The number of mouse embryos found alive during different developmental stages. Csf1r iCre+;Braf LSL-V600E;Rosa26LSL-YFP mice are associated with 100% lethality beyond E14.5. e, Liver weight of E12.5 embryos. Circles represent individual mice. n = 8 for WT;cre−, n = 14 for VE;cre−, n = 16 for VE;cre−, n = 12 for VE;cre+. One-way ANOVA. f, Flow cytometry analysis of Lin−Kit+ blast, erythroid cell (Ter119) and haematopoietic stem cell numbers (LSK CD150+CD48− and CD150−CD48−) in the E12.5 fetal liver and of E12.5 tissue-resident macrophages in the limbs, head and liver. Circles represent individual mice. n = 4 for Braf WT and n = 6 for Braf VE. Unpaired two-tailed t-test.
Extended Data Figure 3 Analysis of the CD11cCre;Braf V600E mouse model.
a, Kaplan–Meier survival curve of Braf VE (n = 16) and Braf WT (n = 66) controls. Log-rank (Mantel–Cox) test. b, Representative photographs of lung and spleen from Braf VE mice at time of death with representative Braf WT control organs. c, d, Haematoxylin and eosin staining of lung tissue from Braf VE and littermate controls. e, CD68 immunohistochemistry of Braf VE lung tissue. f, Haematoxylin and eosin staining of liver tissue from Braf VE and littermate controls with magnified image of granuloma in the Braf VE liver. g, Haematoxylin and eosin staining of bone marrow (BM) of Braf VE and littermate controls with CD68 immunohistochemistry of Braf VE mouse tissue. All images for b–g are representative of n = 5 per genotype.
Extended Data Figure 4 Longitudinal study and PLX treatment of the Csf1r MeriCreMer;Braf V600E;Rosa26 LSL-YFP mice.
a, b, Latency to fall in the rotarod assay and footprint assay quantification for Braf VE mice (n = 7) and Braf WT littermates (n = 8). a, Rotarod assay at 1–4 months of age. Values are mean ± s.d. b, Rotarod and footprint assay at 4 months of age displaying single values. Mice that are score 1 are labelled in red. c, Footprint assay quantification of Braf VE mice at score 1 and littermate controls. Circles represent individual mice. n = 10 for Braf WT and n = 11 for Braf VE. d, Representative weight curves of Braf WT and Braf VE mice on control or PLX4720 diet. e, PLX4720 concentration in serum (ng ml−1), liver and brain (ng g−1) of 7–9-month-old Braf WT (n = 9) and Braf VE mice placed on the diet at 1 (n = 8) or at 3 months (n = 3) of age. Circles represent individual mice. f, Footprint assay quantification from Braf VE mice on PLX4720 diet at 1 month (n = 8) or at 3 months (n = 6) and control (Ctrl) diet (n = 13) and Braf WT (n = 32, black). Mice reaching paralysis were excluded from further analysis. See also g, where the dagger (†) indicates when Braf VE animals were euthanized. Values are mean ± s.d. Two-way ANOVA comparing treated and untreated Braf VE mice. *P < 0.05. g, Disease progression of Braf VE mice on control or PLX4720 diet. †Animal euthanasia owing to paralysis.
Extended Data Figure 5 Microglia activation in the brain starts at early, preclinical stages.
a, Histological analysis by haematoxylin and eosin (HE) and luxol fast blue–PAS (LFB–PAS) and immunohistochemistry analysis of T cells (CD3), B cells (B220) and astrocyte activation (GFAP) in one-month-old Braf VE mice and Braf WT littermates. Representative of n = 5 Braf WT and n = 4 Braf VE mice. b, Immunohistochemistry analysis and quantification of IBA1+ cell density, cortical neurons (NeuN) and expression of amyloid precursor protein (APP), a positive signal for neurodegeneration in one-month-old Braf VE mice and Braf WT. Representative of n = 5 Braf WT and n = 4 Braf VE mice. Circles represent individual mice. Scale bars, 100 μm and 10 μm (insets). Unpaired two-tailed t-test.
Extended Data Figure 6 The neurodegenerative process in Braf VE mice.
a, IBA1 and GFAP immunohistochemistry of brain and spinal cord from six-month-old Braf VE and Braf WT mice. Anatomical regions of insets are indicated. Representative of n = 5 Braf WT and n = 4 Braf VE mice. Scale bars, 500 μm (spinal cords), 1 mm (brains) and 50 μm (insets). b, Immunohistochemistry and immunofluorescence as used for quantification in Fig. 2h of brain stem for NeuN (neurons), APP (amyloid precursor protein) and GFAP (astrocytes), IBA1+LAMP2+ cells (phagocytosis), synaptophysin (Syn) and homer1 (synapse density) and staining with LFB–PAS. Scale bars, 100 μm and 10 μm (insets); 25 μm (IBA1 LAMP2); 10 μm (Syn Homer1). Representative of 6–9-month old Braf WT (n = 5), Braf VE (n = 4) mice and Braf VE mice on the PLX4720 diet (n = 4–6). c, LFB staining of spinal cord samples from a. Scale bar, 100 μm. d, Immunohistochemistry of brain stem for B220 (B cells) from Braf VE on control and PLX4720 diet. Representative of n = 4 mice per genotype. Scale bars, 100 μm and 10 μm (insets).
Extended Data Figure 7 Microglia and T-cell phenotype in Braf VE mice.
a, Representative pERK staining in IBA1+ microglia as used for the quantification in Fig. 3b in brain stems of 5–9-month-old Braf WT and Braf VE mice on control or PLX4720 diet. Scale bar, 50 μm. b, Representative t-SNE analysis of flow cytometry staining of CD45+ cells from the brain of paralyzed Braf VE mice and littermate controls. Arrow indicates expansion of F4/80+YFP+ cells. Representative of n = 3 mice per genotype. c, FSC profile of YFP+ and YFP− microglia from b obtained from Braf VE and Braf WT mice indicates an increase in YFP+ microglia cell size. Representative of n = 3 mice per genotype. d, Proportion of YFP+F4/80+ cells in indicated organs analysed by flow cytometry. The proportion of YFP+ among F4/80+ cells from Braf WTcre+ on control diet was normalized and set to one. Analysis was performed on 5–8-month-old Braf VE mice (n = 5–6) and Braf WT mice (n = 6) on control diet, and 7–9-month-old Braf VE mice (n = 6) and Braf WT mice (n = 4) on PLX4720 diet. Circles represent values for individual mice. One-way ANOVA. *P < 0.05, **P < 0.01. e, CD3 immunohistochemistry of brain and spinal cord of 6-month-old Braf VE and Braf WT mice. Anatomical regions of insets are indicated. Representative of n = 5 Braf WT and n = 4 Braf VE mice. Scale bars, 500 μm (spinal cords), 1 mm (brains) and 50 μm (insets). f, g, Analysis of CD8+, CD4+ and Foxp3+ T-cell numbers (f) and proliferation (g) in brain and spinal cord by flow cytometry in 5–8-month-old Braf VE (n = 4) and Braf WT (n = 6) mice on control diet, and 7–9-month-old Braf VE (n = 6) and Braf WT (n = 5) mice on PLX diet. Circles represent values for individual mice. One-way ANOVA.
Extended Data Figure 8 Analysis of Braf VE mice outside the central nervous system.
a, Proportion of YFP+F4/80+ cells in indicated organs analysed by flow cytometry. The proportion of YFP+ cells among F4/80+ cells from Braf WTcre+ (n = 6) was normalized and set to one (dotted line). Circles represent values for individual Braf VE mice (n = 7). Unpaired two-tailed t-test. b, Analysis of liver Kupffer cells as in a was performed on tissues from 5–8-month-old Braf VE (n = 5) and Braf WT (n = 4) mice on control diet, and 7–9-month-old Braf VE (n = 6) and Braf WT (n = 4) mice on PLX4720 diet. Circles represent values for individual mice. One-way ANOVA. *P < 0.05. c, Immunofluorescence analysis of pERK in F4/80+ Kupffer cells from 5–8-month-old Braf VE mice. Results are representative of n = 3. d, Serum analysis of Braf VE mice (score 1, n = 6) and littermate controls (n = 6). ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase. e, Gross liver, lung, kidney and spleen structure (haematoxylin and eosin, Trichrome) of paralyzed Braf VE and Braf WT mice. Representative of n = 7 mice per genotype. Scale bars, 200 μm and 10 μm (insets). f, Liver and spleen gross organs from paralyzed Braf VE and Braf WT mice. Representative of n = 5 mice per genotype.
Extended Data Figure 9 Patients with ECD.
a, Table summarizing observed pathological and molecular findings in brain tissue of three patients with ECD with neurologic presentations. BRAF status was determined by immunohistochemical analysis and by sequencing. Neuronal loss and demyelination was determined by immunohistochemistry of neurofilament and myelin basic protein (MBP). RF, Rosenthal fibre. n/a, not applicable/no tissue available for further analysis. b, Immunohistochemistry and immmunofluorescence analysis of brain tissue from a patient with ECD for CD163, pERK and BRAF(V600E) (anti-BRAF-VE1 antibody). Scale bars, 200 μm (top) and 5 μm (bottom). c, Immunohistochemistry analysis of brain tissue from a patient with ECD for neurofilament and MBP shows areas of myelin deficits with preserved axons in the same region. Scale bar, 200 μm.
This file contains Supplementary Figure 1 (gel source data) and Supplementary Figure 2 which shows the gating strategy for different tissues and cell types. (PDF 2929 kb)
Supplementary Table 1
RNA-seq analysis, complement to figure 1: list of genes differentially expressed in macrophages from one-month old BRAFVE and BRAFWT littermates (FACS-sorted microglia and Kupffer cells). (XLSX 399 kb)
Supplementary Table 2
RNA-seq analysis, complement to figure 1: GSEA, GO, KEGG and REACTOME analysis of differentially expressed genes in microglia and Kupffer cells in one-month old BRAFVE and BRAFWT littermates. (XLSX 125 kb)
Supplementary Table 3
RNA-seq analysis, complement to figure 4: list of genes differentially expressed and GSEA and KEGG analysis in YFP+ microglia from 7 months-old BRAFVE and BRAFWT littermates. (XLSX 1295 kb)
Supplementary Table 4
Differentially expressed genes from RNA-seq of brain tissue from control and histiocytosis patients. (XLSX 2401 kb)
Supplementary Table 5
A list of antibodies used for flow cytometry. (XLSX 40 kb)
Supplementary Table 6
Clinical and pathological characteristics of human tissue samples from ECD patients and age-matched controls (XLSX 10 kb)
Video 1: Hind limb paresis, 7-month-old BRAFVE mouse
This video shows hind limb paresis in a 7-month-old BRAFVE mouse. (MOV 3905 kb)
Video 2: Axial rolling, 4-month-old BRAFVE mouse
This video shows axial rolling in 4-month-old BRAFVE mouse (labelled by the black spot). (MOV 5412 kb)
Video 3: Hind limb paralysis of an 8-month-old BRAFVE mouse.
This video shows hind limb paralysis of an 8-month-old BRAFVE mouse. (MOV 4044 kb)
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Mass, E., Jacome-Galarza, C., Blank, T. et al. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549, 389–393 (2017). https://doi.org/10.1038/nature23672
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