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@ARTICLE{Miedema:164917,
      author       = {Miedema, Suzanne S M and Mol, Merel O and Koopmans, Frank T
                      W and Hondius, David C and van Nierop, Pim and Menden, Kevin
                      and de Veij Mestdagh, Christina F and van Rooij, Jeroen and
                      Ganz, Andrea B and Paliukhovich, Iryna and Melhem, Shamiram
                      and Li, Ka Wan and Holstege, Henne and Rizzu, Patrizia and
                      van Kesteren, Ronald E and van Swieten, John C and Heutink,
                      Peter and Smit, August B},
      title        = {{D}istinct cell type-specific protein signatures in {GRN}
                      and {MAPT} genetic subtypes of frontotemporal dementia.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {10},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2022-01328},
      pages        = {100},
      year         = {2022},
      note         = {CC BY},
      abstract     = {Frontotemporal dementia is characterized by progressive
                      atrophy of frontal and/or temporal cortices at an early age
                      of onset. The disorder shows considerable clinical,
                      pathological, and genetic heterogeneity. Here we
                      investigated the proteomic signatures of frontal and
                      temporal cortex from brains with frontotemporal dementia due
                      to GRN and MAPT mutations to identify the key cell types and
                      molecular pathways in their pathophysiology. We compared
                      patients with mutations in the GRN gene (n = 9) or with
                      mutations in the MAPT gene (n = 13) with non-demented
                      controls (n = 11). Using quantitative proteomic analysis on
                      laser-dissected tissues we identified brain region-specific
                      protein signatures for both genetic subtypes. Using
                      published single cell RNA expression data resources we
                      deduced the involvement of major brain cell types in driving
                      these different protein signatures. Subsequent gene ontology
                      analysis identified distinct genetic subtype- and cell
                      type-specific biological processes. For the GRN subtype, we
                      observed a distinct role for immune processes related to
                      endothelial cells and for mitochondrial dysregulation in
                      neurons. For the MAPT subtype, we observed distinct
                      involvement of dysregulated RNA processing, oligodendrocyte
                      dysfunction, and axonal impairments. Comparison with an
                      in-house protein signature of Alzheimer's disease brains
                      indicated that the observed alterations in RNA processing
                      and oligodendrocyte function are distinct for the
                      frontotemporal dementia MAPT subtype. Taken together, our
                      results indicate the involvement of different brain cell
                      types and biological mechanisms in genetic subtypes of
                      frontotemporal dementia. Furthermore, we demonstrate that
                      comparison of proteomic profiles of different disease
                      entities can separate general neurodegenerative processes
                      from disease-specific pathways, which may aid the
                      development of disease subtype-specific treatment
                      strategies.},
      keywords     = {Endothelial Cells: metabolism / Frontotemporal Dementia:
                      genetics / Frontotemporal Dementia: pathology / Humans /
                      Intercellular Signaling Peptides and Proteins: genetics /
                      Mutation: genetics / Pick Disease of the Brain /
                      Progranulins: genetics / Proteomics / tau Proteins: genetics
                      / tau Proteins: metabolism / Cell type enrichment (Other) /
                      Frontotemporal dementia (Other) / GRN (Other) / Human brain
                      proteomics (Other) / MAPT (Other) / GRN protein, human (NLM
                      Chemicals) / Intercellular Signaling Peptides and Proteins
                      (NLM Chemicals) / MAPT protein, human (NLM Chemicals) /
                      Progranulins (NLM Chemicals) / tau Proteins (NLM Chemicals)},
      cin          = {AG Heutink 1 / AG Rizzu},
      ddc          = {610},
      cid          = {I:(DE-2719)1210002 / I:(DE-2719)1210009},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35799292},
      pmc          = {pmc:PMC9261008},
      doi          = {10.1186/s40478-022-01387-8},
      url          = {https://pub.dzne.de/record/164917},
}