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@ARTICLE{Huber:285263,
      author       = {Huber, Nadine and Hietanen, Tomi and Heikkinen, Sami and
                      Shakirzyanova, Anastasia and Hoffmann, Dorit and Rostalski,
                      Hannah and Dhingra, Ashutosh and Rodriguez-Nieto, Salvador
                      and Kärkkäinen, Sari and Koskuvi, Marja and Korhonen, Eila
                      and Hartikainen, Päivi and Pylkäs, Katri and Krüger,
                      Johanna and Malm, Tarja and Takalo, Mari and Hiltunen, Mikko
                      and Koistinaho, Jari and Portaankorva, Anne M and Solje,
                      Eino and Haapasalo, Annakaisa},
      title        = {{F}rontotemporal dementia patient-derived i{PSC} neurons
                      show cell pathological hallmarks and evidence for synaptic
                      dysfunction and {DNA} damage.},
      journal      = {Molecular psychiatry},
      volume       = {31},
      number       = {3},
      issn         = {1359-4184},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2026-00205},
      pages        = {1500 - 1516},
      year         = {2026},
      abstract     = {Frontotemporal dementia (FTD) is the second most common
                      cause of dementia in patients under 65 years, characterized
                      by diverse clinical symptoms, neuropathologies, and genetic
                      background. Synaptic dysfunction is suggested to play a
                      major role in FTD pathogenesis. Disturbances in the synaptic
                      function can also be associated with the C9orf72 repeat
                      expansion (C9-HRE), the most common genetic mutation causing
                      FTD. C9-HRE leads to distinct pathological hallmarks, such
                      as C9orf72 haploinsufficiency and development of toxic RNA
                      foci and dipeptide repeat proteins (DPRs). FTD patient
                      brains, including those carrying the C9-HRE, are also
                      characterized by neuropathologies involving accumulation of
                      TDP-43 and p62/SQSTM1 proteins. This study utilized induced
                      pluripotent stem cell (iPSC)-derived cortical neurons from
                      C9-HRE-carrying or sporadic FTD patients and healthy control
                      individuals. We report that the iPSC neurons derived from
                      C9-HRE carriers developed typical C9-HRE-associated
                      hallmarks, including RNA foci and DPR accumulation. All FTD
                      neurons demonstrated increased cytosolic accumulation of
                      TDP-43 and p62/SQSTM1 and changes in nuclear size and
                      morphology. In addition, the FTD neurons displayed reduced
                      number and altered morphologies of dendritic spines and
                      significantly altered synaptic function indicated by a
                      decreased response to stimulation with GABA. These
                      structural and functional synaptic disturbances were
                      accompanied by upregulated gene expression in the FTD
                      neurons related to synaptic function, including synaptic
                      signaling, glutamatergic transmission, and pre- and
                      postsynaptic membrane, as compared to control neurons.
                      Pathways involved in DNA repair were significantly
                      downregulated in FTD neurons. Only one gene, NUPR2,
                      potentially involved in DNA damage response, was
                      differentially expressed between the sporadic and
                      C9-HRE-carrying FTD neurons. Our results show that the iPSC
                      neurons from FTD patients recapitulate pathological changes
                      of the FTD brain and strongly support the hypothesis of
                      synaptic dysfunction as a crucial contributor to disease
                      pathogenesis in FTD.},
      keywords     = {Humans / Induced Pluripotent Stem Cells: metabolism /
                      Induced Pluripotent Stem Cells: pathology / Frontotemporal
                      Dementia: genetics / Frontotemporal Dementia: pathology /
                      Frontotemporal Dementia: metabolism / Neurons: metabolism /
                      Neurons: pathology / C9orf72 Protein: genetics / C9orf72
                      Protein: metabolism / DNA Damage: genetics / DNA Damage:
                      physiology / Synapses: metabolism / Synapses: pathology /
                      DNA-Binding Proteins: metabolism / DNA-Binding Proteins:
                      genetics / Male / Female / Sequestosome-1 Protein:
                      metabolism / Middle Aged / Aged / DNA Repeat Expansion:
                      genetics / Brain: metabolism / C9orf72 Protein (NLM
                      Chemicals) / DNA-Binding Proteins (NLM Chemicals) /
                      Sequestosome-1 Protein (NLM Chemicals) / SQSTM1 protein,
                      human (NLM Chemicals) / C9orf72 protein, human (NLM
                      Chemicals) / TARDBP protein, human (NLM Chemicals)},
      cin          = {AG Heutink},
      ddc          = {610},
      cid          = {I:(DE-2719)1210002},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41006764},
      doi          = {10.1038/s41380-025-03272-x},
      url          = {https://pub.dzne.de/record/285263},
}