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@ARTICLE{Domingues:282964,
      author       = {Domingues, Neuza and Calcagni', Alessia and Freire, Sofia
                      and Pires, Joana and Casqueiro, Ricardo and Salazar, Ivan L
                      and Herz, Niculin Joachim and Huynh, Tuong and Wieciorek,
                      Katarzyna and Outeiro, Tiago Fleming and Girão, Henrique
                      and Milosevic, Ira and Ballabio, Andrea and Raimundo, Nuno},
      title        = {{L}oss of the lysosomal protein {CLN}3 triggers
                      c-{A}bl-dependent {YAP}1 pro-apoptotic signaling.},
      journal      = {EMBO reports},
      volume       = {26},
      number       = {24},
      issn         = {1469-221X},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2025-01416},
      pages        = {6096 - 6120},
      year         = {2025},
      abstract     = {Batten disease is characterized by early-onset blindness,
                      juvenile dementia and death within the second decade of
                      life. The most common genetic cause are mutations in CLN3,
                      encoding a lysosomal protein. Currently, no therapies
                      targeting disease progression are available, largely because
                      its molecular mechanisms remain poorly understood. To
                      understand how CLN3 loss affects cellular signaling, we
                      generated human CLN3 knock-out cells (CLN3-KO) and performed
                      RNA-seq analysis. Our multi-dimensional analysis reveals the
                      transcriptional regulator YAP1 as a key factor in remodeling
                      the transcriptome in CLN3-KO cells. YAP1-mediated
                      pro-apoptotic signaling is also increased as a consequence
                      of CLN3 functional loss in retinal pigment epithelia cells,
                      and in the hippocampus and thalamus of Cln3Δ7/8 mice, an
                      established model of Batten disease. Loss of CLN3 leads to
                      DNA damage, activating the kinase c-Abl which phosphorylates
                      YAP1, stimulating its pro-apoptotic signaling. This novel
                      molecular mechanism underlying the loss of CLN3 in mammalian
                      cells and tissues may pave a way for novel c-Abl-centric
                      therapeutic strategies to target Batten disease.},
      keywords     = {Animals / YAP-Signaling Proteins / Humans / Signal
                      Transduction / Mice / Apoptosis: genetics / Adaptor
                      Proteins, Signal Transducing: metabolism / Adaptor Proteins,
                      Signal Transducing: genetics / Proto-Oncogene Proteins
                      c-abl: metabolism / Proto-Oncogene Proteins c-abl: genetics
                      / Membrane Glycoproteins: genetics / Membrane Glycoproteins:
                      metabolism / Molecular Chaperones: genetics / Molecular
                      Chaperones: metabolism / Neuronal Ceroid-Lipofuscinoses:
                      genetics / Neuronal Ceroid-Lipofuscinoses: metabolism /
                      Neuronal Ceroid-Lipofuscinoses: pathology / Lysosomes:
                      metabolism / Mice, Knockout / Retinal Pigment Epithelium:
                      metabolism / Disease Models, Animal / Batten Disease (Other)
                      / DNA Damage (Other) / Lysosome-Nucleus Communication
                      (Other) / Lysosomes (Other) / YAP1 (Other) / YAP-Signaling
                      Proteins (NLM Chemicals) / Adaptor Proteins, Signal
                      Transducing (NLM Chemicals) / YAP1 protein, human (NLM
                      Chemicals) / Proto-Oncogene Proteins c-abl (NLM Chemicals) /
                      Membrane Glycoproteins (NLM Chemicals) / Molecular
                      Chaperones (NLM Chemicals) / CLN3 protein, human (NLM
                      Chemicals) / Yap1 protein, mouse (NLM Chemicals)},
      cin          = {AG Fischer},
      ddc          = {570},
      cid          = {I:(DE-2719)1410002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC12714701},
      pubmed       = {pmid:41198904},
      doi          = {10.1038/s44319-025-00613-3},
      url          = {https://pub.dzne.de/record/282964},
}