Neuronal vulnerability and multilineage diversity in multiple sclerosis
| Autor: | Maike Steindel, Dorothy P. Schafer, Omer Ali Bayraktar, Jan Broder Engler, Dmitry Velmeshev, Lawrence R. Shiow, Aparna Bhaduri, Richard Reynolds, David H. Rowitch, John H. Stockley, Maximilian Haeussler, Max Kaufmann, Brian Tung, Nitasha Goyal, Stephanie Vistnes, Arnold R. Kriegstein, Robin J.M. Franklin, Diane Jung, Manuel A. Friese, Simone Mayer, Sebastian Werneburg, Staffan Holmqvist, Lucas Schirmer, Adam Young |
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| Přispěvatelé: | Holmqvist, Staffan [0000-0001-6709-6666], Stockley, John [0000-0002-7385-8310], Franklin, Robin [0000-0001-6522-2104], Rowitch, David [0000-0002-0079-0060], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Neurodegenerative DISEASE Myelin Mice 0302 clinical medicine DEMYELINATION RNA Small Nuclear 2.1 Biological and endogenous factors RNA-Seq Aetiology Myelin Sheath Neurons Multidisciplinary Microglia Neurodegeneration Middle Aged Cell biology Multidisciplinary Sciences Oligodendroglia medicine.anatomical_structure Neurological Science & Technology - Other Topics Female Autopsy Biotechnology Adult Multiple Sclerosis General Science & Technology In situ hybridization Biology Autoimmune Disease Article White matter MICROGLIA 03 medical and health sciences INFLAMMATION Small Nuclear Phagocytosis GRADIENT medicine Genetics Animals Humans Cell Lineage Homeodomain Proteins Cryopreservation Science & Technology LESIONS Multiple sclerosis Macrophages Human Genome Neurosciences medicine.disease Brain Disorders PATHOLOGY 030104 developmental biology Neuroimmunology Astrocytes RNA Neuron Transcriptome 030217 neurology & neurosurgery |
| Zdroj: | Nature, vol 573, iss 7772 Nature |
| Popis: | Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions. |
| Databáze: | OpenAIRE |
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