TY  - JOUR
AU  - Domingues, Neuza
AU  - Calcagni', Alessia
AU  - Freire, Sofia
AU  - Pires, Joana
AU  - Casqueiro, Ricardo
AU  - Salazar, Ivan L
AU  - Herz, Niculin Joachim
AU  - Huynh, Tuong
AU  - Wieciorek, Katarzyna
AU  - Outeiro, Tiago Fleming
AU  - Girão, Henrique
AU  - Milosevic, Ira
AU  - Ballabio, Andrea
AU  - Raimundo, Nuno
TI  - Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.
JO  - EMBO reports
VL  - 26
IS  - 24
SN  - 1469-221X
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2025-01416
SP  - 6096 - 6120
PY  - 2025
AB  - 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.
KW  - Animals
KW  - YAP-Signaling Proteins
KW  - Humans
KW  - Signal Transduction
KW  - Mice
KW  - Apoptosis: genetics
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Proto-Oncogene Proteins c-abl: metabolism
KW  - Proto-Oncogene Proteins c-abl: genetics
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Molecular Chaperones: genetics
KW  - Molecular Chaperones: metabolism
KW  - Neuronal Ceroid-Lipofuscinoses: genetics
KW  - Neuronal Ceroid-Lipofuscinoses: metabolism
KW  - Neuronal Ceroid-Lipofuscinoses: pathology
KW  - Lysosomes: metabolism
KW  - Mice, Knockout
KW  - Retinal Pigment Epithelium: metabolism
KW  - Disease Models, Animal
KW  - Batten Disease (Other)
KW  - DNA Damage (Other)
KW  - Lysosome-Nucleus Communication (Other)
KW  - Lysosomes (Other)
KW  - YAP1 (Other)
KW  - YAP-Signaling Proteins (NLM Chemicals)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - YAP1 protein, human (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-abl (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - CLN3 protein, human (NLM Chemicals)
KW  - Yap1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC12714701
C6  - pmid:41198904
DO  - DOI:10.1038/s44319-025-00613-3
UR  - https://pub.dzne.de/record/282964
ER  -