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@ARTICLE{Alidadiani:280290,
      author       = {Alidadiani, Sara and Faura, Júlia and Wynants, Sarah and
                      Peeters, Nele and Van den Broeck, Marleen and De Witte,
                      Linus and Policarpo, Rafaela and Cheung, Simon and Pottier,
                      Cyril and Ghayal, Nikhil B and Mol, Merel O and van
                      Blitterswijk, Marka and Udine, Evan and DeJesus-Hernandez,
                      Mariely and Baker, Matthew and Finch, NiCole A and Asmann,
                      Yan W and van Rooij, Jeroen G J and Nguyen, Aivi T and Ross
                      Reichard, R. and Nana, Alissa L and Lopez, Oscar L and
                      Boxer, Adam L and Rosen, Howard J and Spina, Salvatore and
                      Herms, Jochen and Josephs, Keith A and Petersen, Ronald C
                      and Rissman, Robert A and Hiniker, Annie and Ang, Lee-Cyn
                      and Grinberg, Lea T and Halliday, Glenda M and Boeve,
                      Bradley F and Graff-Radford, Neill R and Seelaar, Harro and
                      Neumann, Manuela and Kofler, Julia and White, Charles L and
                      Seeley, William W and van Swieten, John C and Dickson,
                      Dennis W and Mackenzie, Ian R A and De Coster, Wouter and
                      Rademakers, Rosa},
      title        = {{B}rain transcriptomics highlight abundant gene expression
                      and splicing alterations in non-neuronal cells in
                      a{FTLD}-{U}.},
      journal      = {Acta neuropathologica},
      volume       = {150},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2025-00945},
      pages        = {17},
      year         = {2025},
      abstract     = {Atypical frontotemporal lobar degeneration with
                      ubiquitin-positive inclusions (aFTLD-U) is a rare cause of
                      frontotemporal lobar degeneration (FTLD), characterized
                      postmortem by neuronal inclusions of the FET family of
                      proteins (FTLD-FET). The recent discovery of TAF15 amyloid
                      filaments in aFTLD-U brains represents a significant step
                      toward improved diagnostic and therapeutic strategies.
                      However, our understanding of the etiology of this FTLD
                      subtype remains limited, which severely hampers
                      translational research efforts. To explore the
                      transcriptomic changes in aFTLD-U, we performed bulk RNA
                      sequencing on the frontal cortex tissue of 21 aFTLD-U
                      patients and 20 control individuals. Cell-type deconvolution
                      revealed loss of excitatory neurons and a higher proportion
                      of astrocytes in aFTLD-U relative to controls. Differential
                      gene expression and co-expression network analysis, adjusted
                      for the shift in cell-type proportions, showed dysregulation
                      of mitochondrial pathways, transcriptional regulators, and
                      upregulation of the Sonic hedgehog (Shh) pathway, including
                      the GLI1 transcription factor, in aFTLD-U. Overall,
                      oligodendrocyte and astrocyte-enriched genes were
                      significantly over-represented among the differentially
                      expressed genes. Differential splicing analysis confirmed
                      the dysregulation of non-neuronal cell types with
                      significant splicing alterations, particularly in
                      oligodendrocyte-enriched genes, including myelin basic
                      protein (MBP), a crucial component of myelin.
                      Immunohistochemistry in frontal cortex brain tissue also
                      showed reduced myelin levels in aFTLD-U patients compared to
                      controls. Together, these findings highlight a central role
                      for glial cells, particularly astrocytes and
                      oligodendrocytes, in the pathogenesis of aFTLD-U, with
                      disruptions in mitochondrial activity, RNA metabolism, Shh
                      signaling, and myelination as possible disease mechanisms.
                      This study offers the first transcriptomic insight into
                      aFTLD-U and presents new avenues for research into
                      FTLD-FET.},
      keywords     = {Humans / Male / Female / Transcriptome / Aged /
                      Frontotemporal Lobar Degeneration: genetics / Frontotemporal
                      Lobar Degeneration: pathology / Frontotemporal Lobar
                      Degeneration: metabolism / Middle Aged / Brain: metabolism /
                      Brain: pathology / Neurons: metabolism / Neurons: pathology
                      / RNA Splicing / Astrocytes: metabolism / Glial cells
                      (Other) / Mitochondria (Other) / Sonic hedgehog signaling
                      (Other) / Splicing (Other) / Transcriptomics (Other) /
                      aFTLD-U (Other)},
      cin          = {AG Herms / AG Neumann},
      ddc          = {610},
      cid          = {I:(DE-2719)1110001 / I:(DE-2719)1210003},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40783910},
      doi          = {10.1007/s00401-025-02919-x},
      url          = {https://pub.dzne.de/record/280290},
}