Neuronal vulnerability and multilineage diversity in multiple sclerosis. Schirmer, L., Velmeshev, D., Holmqvist, S., Kaufmann, M., Werneburg, S., Jung, D., Vistnes, S., Stockley, J. H, Young, A., Steindel, M., Tung, B., Goyal, N., Bhaduri, A., Mayer, S., Engler, J. B., Bayraktar, O. A, Franklin, R. J M, Haeussler, M., Reynolds, R., Schafer, D. P, Friese, M. A, Shiow, L. R, Kriegstein, A. R, & Rowitch, D. H Nature, 573(7772):75–82, July, 2019.
abstract   bibtex   
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.
@ARTICLE{Schirmer2019-jc,
  title    = "Neuronal vulnerability and multilineage diversity in multiple
              sclerosis",
  author   = "Schirmer, Lucas and Velmeshev, Dmitry and Holmqvist, Staffan and
              Kaufmann, Max and Werneburg, Sebastian and Jung, Diane and
              Vistnes, Stephanie and Stockley, John H and Young, Adam and
              Steindel, Maike and Tung, Brian and Goyal, Nitasha and Bhaduri,
              Aparna and Mayer, Simone and Engler, Jan Broder and Bayraktar,
              Omer A and Franklin, Robin J M and Haeussler, Maximilian and
              Reynolds, Richard and Schafer, Dorothy P and Friese, Manuel A and
              Shiow, Lawrence R and Kriegstein, Arnold R and Rowitch, David H",
  abstract = "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.",
  journal  = "Nature",
  volume   =  573,
  number   =  7772,
  pages    = "75--82",
  month    =  jul,
  year     =  2019,
  language = "en"
}

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