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      A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

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          Abstract

          The pathophysiology of neurodegenerative diseases is poorly understood, and therapeutic options are few. Neurodegenerative diseases are hallmarked by progressive neuronal dysfunction and loss, associated with chronic glial activation 1 . Whether microglial activation, which is viewed in general as a secondary process, is detrimental or protective in neurodegeneration remains unclear 18 . Late-onset neurodegenerative disease observed in patients with histiocytoses 912 , which are clonal myeloid diseases associated with somatic mutations in the RAS/MEK/ERK pathway such as BRAF V600E 1317 , suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet expression of BRAF V600E in the hematopoietic stem cell (HSC) lineage causes leukemic and tumoral diseases but not neurodegenerative disease 18, 19 . Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk sac erythro-myeloid progenitors (EMP) distinct from HSC 2023 . We thus hypothesized that a somatic BRAF V600E mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF V600E in EMP results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder, associated with accumulation of ERK-activated amoeboid microglia in mice, also observed in human histiocytoses patients. In the murine model, neurobehavioral signs, astrogliosis, amyloid precursor protein deposition, 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 in mice that a somatic mutation in the EMP lineage can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration, and provide opportunities for therapeutic intervention aimed at preventing neuronal death in neurodegenerative diseases.

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          Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

          Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch–RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8− DC subset and reduced the frequency of cytokine-secreting CD8− DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J–deficient splenic CD8− DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8− DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch–RBP-J signaling controls the maintenance of CD8− DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
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            Sailfish enables alignment-free isoform quantification from RNA-seq reads using lightweight algorithms

            We introduce Sailfish, a computational method for quantifying the abundance of previously annotated RNA isoforms from RNA-seq data. Because Sailfish entirely avoids mapping reads, a time-consuming step in all current methods, it provides quantification estimates much faster than do existing approaches (typically 20 times faster) without loss of accuracy. By facilitating frequent reanalysis of data and reducing the need to optimize parameters, Sailfish exemplifies the potential of lightweight algorithms for efficiently processing sequencing reads.
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              High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.

              Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAF(V600) mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAF(V600E) mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAF(V600E) histiocytosis.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                14 November 2017
                30 August 2017
                21 September 2017
                16 July 2018
                : 549
                : 7672
                : 389-393
                Affiliations
                [1 ]Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                [2 ]Institute of Neuropathology, Faculty of Medicine, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany
                [3 ]Human Oncology and Pathogenesis Program, Leukemia Service, Dept. of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                [4 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                [5 ]Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK
                Author notes
                [* ] Corresponding author: Frederic Geissmann, MD PhD. Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA. geissmaf@ 123456mskcc.org
                [$]

                These authors contributed equally to this work

                [§]

                These authors jointly supervised this work

                Article
                NIHMS895894
                10.1038/nature23672
                6047345
                28854169
                13a50ded-c715-4ddd-a097-4de79c0b88ba

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