biostudies-literatureDomingues NDeutsche Forschungsgemeinschaft (DFG)HHS | National Institutes of Health (NIH)EC | Horizon 2020 Framework Programme (H2020)MEC | Fundação para a Ciência e a TecnologiaEC | Horizon 2020 Framework ProgrammeFondazione Telethon (FT)Comissão de Coordenação e Desenvolvimento Regional do Centro - CCDRC through the Centro2020 ProgrammeNCL-Stiftung&apos;la Caixa&apos; FoundationJohn Black FoundationAssociazione Italiana per la Ricerca sul Cancro A.I.R.CHHS | National Institutes of HealthDeutsche ForschungsgemeinschaftEuropean Research CouncilTelethonMEC | Fundação para a Ciência e a Tecnologia (FCT)NCI NIH HHSWellcome Trust6096-6120https://www.ebi.ac.uk/biostudies/studies/S-EPMC12714701biostudies-literatureUnknown26(24)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 Cln3<sup>Δ7EMBO reportsLoss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.PMC12714701SFB1190-P02IG-22103R01-CA2602058575242022.09311.PTDC224361/Z/21/ZR01 CA260205H2023 AdG; INCANTAR 101097752337327Pires JSalazar ILMilosevic ICasqueiro RCalcagni' AHerz NJDomingues NWieciorek KOuteiro TFFreire SGirao HHuynh TBallabio ARaimundo NfalseLoss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.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 Cln3<sup>Δ72025-01-01T00:00:00Z2025 Dec2026-06-18T05:49:49.571Z2026-06-18T03:07:43.698ZS-EPMC127147014119890410.1038/s44319-025-00613-3