2. Academic Validation
  3. Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling

Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling

  • EMBO Rep. 2025 Dec;26(24):6096-6120. doi: 10.1038/s44319-025-00613-3.
Neuza Domingues 1,  Alessia Calcagni' 2 3,  Sofia Freire 4,  Joana Pires 4,  Ricardo Casqueiro 4,  Ivan L Salazar 4,  Niculin Joachim Herz 5 6,  Tuong Huynh 5 6,  Katarzyna Wieciorek 7,  Tiago Fleming Outeiro 7 8 9 10,  Henrique Girão 11,  Ira Milosevic 4 12,  Andrea Ballabio 2 3 5 6 13,  Nuno Raimundo 14 15 16
Affiliations

Affiliations

  • 1 Multidisciplinary Institute of Ageing, Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. [email protected].
  • 2 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
  • 3 Department of Translational Medical Sciences, Federico II University, Naples, Italy.
  • 4 Multidisciplinary Institute of Ageing, Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 6 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
  • 7 University Medical Center Göttingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Göttingen, Germany.
  • 8 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 9 Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • 10 Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany.
  • 11 Coimbra Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology, Academic and Clinical Center of Coimbra, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
  • 12 Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 13 SSM School for Advanced Studies, Federico II University, Naples, Italy.
  • 14 Multidisciplinary Institute of Ageing, Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. [email protected].
  • 15 Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA. [email protected].
  • 16 Penn State Cancer Institute, Hershey, PA, USA. [email protected].
PMID: 41198904 DOI: 10.1038/s44319-025-00613-3
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

Batten Disease; DNA Damage; Lysosome-Nucleus Communication; Lysosomes; YAP1.

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