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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H"],"bibdata":{"bibtype":"article","type":"article","title":"Neuronal vulnerability and multilineage diversity in multiple sclerosis","author":[{"propositions":[],"lastnames":["Schirmer"],"firstnames":["Lucas"],"suffixes":[]},{"propositions":[],"lastnames":["Velmeshev"],"firstnames":["Dmitry"],"suffixes":[]},{"propositions":[],"lastnames":["Holmqvist"],"firstnames":["Staffan"],"suffixes":[]},{"propositions":[],"lastnames":["Kaufmann"],"firstnames":["Max"],"suffixes":[]},{"propositions":[],"lastnames":["Werneburg"],"firstnames":["Sebastian"],"suffixes":[]},{"propositions":[],"lastnames":["Jung"],"firstnames":["Diane"],"suffixes":[]},{"propositions":[],"lastnames":["Vistnes"],"firstnames":["Stephanie"],"suffixes":[]},{"propositions":[],"lastnames":["Stockley"],"firstnames":["John","H"],"suffixes":[]},{"propositions":[],"lastnames":["Young"],"firstnames":["Adam"],"suffixes":[]},{"propositions":[],"lastnames":["Steindel"],"firstnames":["Maike"],"suffixes":[]},{"propositions":[],"lastnames":["Tung"],"firstnames":["Brian"],"suffixes":[]},{"propositions":[],"lastnames":["Goyal"],"firstnames":["Nitasha"],"suffixes":[]},{"propositions":[],"lastnames":["Bhaduri"],"firstnames":["Aparna"],"suffixes":[]},{"propositions":[],"lastnames":["Mayer"],"firstnames":["Simone"],"suffixes":[]},{"propositions":[],"lastnames":["Engler"],"firstnames":["Jan","Broder"],"suffixes":[]},{"propositions":[],"lastnames":["Bayraktar"],"firstnames":["Omer","A"],"suffixes":[]},{"propositions":[],"lastnames":["Franklin"],"firstnames":["Robin","J","M"],"suffixes":[]},{"propositions":[],"lastnames":["Haeussler"],"firstnames":["Maximilian"],"suffixes":[]},{"propositions":[],"lastnames":["Reynolds"],"firstnames":["Richard"],"suffixes":[]},{"propositions":[],"lastnames":["Schafer"],"firstnames":["Dorothy","P"],"suffixes":[]},{"propositions":[],"lastnames":["Friese"],"firstnames":["Manuel","A"],"suffixes":[]},{"propositions":[],"lastnames":["Shiow"],"firstnames":["Lawrence","R"],"suffixes":[]},{"propositions":[],"lastnames":["Kriegstein"],"firstnames":["Arnold","R"],"suffixes":[]},{"propositions":[],"lastnames":["Rowitch"],"firstnames":["David","H"],"suffixes":[]}],"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":"July","year":"2019","language":"en","bibtex":"@ARTICLE{Schirmer2019-jc,\n title = \"Neuronal vulnerability and multilineage diversity in multiple\n sclerosis\",\n author = \"Schirmer, Lucas and Velmeshev, Dmitry and Holmqvist, Staffan and\n Kaufmann, Max and Werneburg, Sebastian and Jung, Diane and\n Vistnes, Stephanie and Stockley, John H and Young, Adam and\n Steindel, Maike and Tung, Brian and Goyal, Nitasha and Bhaduri,\n Aparna and Mayer, Simone and Engler, Jan Broder and Bayraktar,\n Omer A and Franklin, Robin J M and Haeussler, Maximilian and\n Reynolds, Richard and Schafer, Dorothy P and Friese, Manuel A and\n Shiow, Lawrence R and Kriegstein, Arnold R and Rowitch, David H\",\n abstract = \"Multiple sclerosis (MS) is a neuroinflammatory disease with a\n relapsing-remitting disease course at early stages, distinct\n lesion characteristics in cortical grey versus subcortical white\n matter and neurodegeneration at chronic stages. Here we used\n single-nucleus RNA sequencing to assess changes in expression in\n multiple cell lineages in MS lesions and validated the results\n using multiplex in situ hybridization. We found selective\n vulnerability and loss of excitatory CUX2-expressing projection\n neurons in upper-cortical layers underlying meningeal\n inflammation; such MS neuron populations exhibited upregulation\n of stress pathway genes and long non-coding RNAs. Signatures of\n stressed oligodendrocytes, reactive astrocytes and activated\n microglia mapped most strongly to the rim of MS plaques. Notably,\n single-nucleus RNA sequencing identified phagocytosing microglia\n and/or macrophages by their ingestion and perinuclear import of\n myelin transcripts, confirmed by functional mouse and human\n culture assays. Our findings indicate lineage- and\n region-specific transcriptomic changes associated with selective\n cortical neuron damage and glial activation contributing to\n progression of MS lesions.\",\n journal = \"Nature\",\n volume = 573,\n number = 7772,\n pages = \"75--82\",\n month = jul,\n year = 2019,\n language = \"en\"\n}\n\n","author_short":["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. 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