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@ARTICLE{Briel:165111,
      author       = {Briel, Nils and Ruf, Viktoria C and Pratsch, Katrin and
                      Roeber, Sigrun and Widmann, Jeannine and Mielke, Janina and
                      Dorostkar, Mario Manucehr and Windl, Otto and Arzberger,
                      Thomas and Herms, Jochen and Strübing, Felix},
      title        = {{S}ingle-nucleus chromatin accessibility profiling
                      highlights distinct astrocyte signatures in progressive
                      supranuclear palsy and corticobasal degeneration.},
      journal      = {Acta neuropathologica},
      volume       = {144},
      number       = {4},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2022-01420},
      pages        = {615 - 635},
      year         = {2022},
      abstract     = {Tauopathies such as progressive supranuclear palsy (PSP)
                      and corticobasal degeneration (CBD) exhibit characteristic
                      neuronal and glial inclusions of hyperphosphorylated Tau
                      (pTau). Although the astrocytic pTau phenotype upon
                      neuropathological examination is the most guiding feature in
                      distinguishing both diseases, regulatory mechanisms
                      controlling their transitions into disease-specific states
                      are poorly understood to date. Here, we provide accessible
                      chromatin data of more than 45,000 single nuclei isolated
                      from the frontal cortex of PSP, CBD, and control
                      individuals. We found a strong association of
                      disease-relevant molecular changes with astrocytes and
                      demonstrate that tauopathy-relevant genetic risk variants
                      are tightly linked to astrocytic chromatin accessibility
                      profiles in the brains of PSP and CBD patients. Unlike the
                      established pathogenesis in the secondary tauopathy
                      Alzheimer disease, microglial alterations were relatively
                      sparse. Transcription factor (TF) motif enrichments in
                      pseudotime as well as modeling of the astrocytic TF
                      interplay suggested a common pTau signature for CBD and PSP
                      that is reminiscent of an inflammatory immediate-early
                      response. Nonetheless, machine learning models also
                      predicted discriminatory features, and we observed marked
                      differences in molecular entities related to protein
                      homeostasis between both diseases. Predicted TF involvement
                      was supported by immunofluorescence analyses in postmortem
                      brain tissue for their highly correlated target genes.
                      Collectively, our data expand the current knowledge on risk
                      gene involvement (e.g., MAPT, MAPK8, and NFE2L2) and
                      molecular pathways leading to the phenotypic changes
                      associated with CBD and PSP.},
      keywords     = {Astrocytes: pathology / Chromatin / Corticobasal
                      Degeneration / Humans / Supranuclear Palsy, Progressive:
                      pathology / Tauopathies: genetics / Tauopathies: pathology /
                      tau Proteins: genetics / tau Proteins: metabolism /
                      Astrocytes (Other) / Corticobasal degeneration (Other) /
                      Neurodegeneration (Other) / Progressive supranuclear palsy
                      (Other) / Tauopathy (Other) / snATAC-seq (Other)},
      cin          = {AG Herms / Neuropathology / Brainbank},
      ddc          = {610},
      cid          = {I:(DE-2719)1110001 / I:(DE-2719)1140013},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9468099},
      pubmed       = {pmid:35976433},
      doi          = {10.1007/s00401-022-02483-8},
      url          = {https://pub.dzne.de/record/165111},
}