Home > Publications Database > Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling. > print

001     282964
005     20260107144731.0
024 7 _ |a pmc:PMC12714701
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024 7 _ |a 10.1038/s44319-025-00613-3
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024 7 _ |a pmid:41198904
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024 7 _ |a 1469-221X
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024 7 _ |a 1469-3178
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037 _ _ |a DZNE-2025-01416
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Domingues, Neuza
|0 0000-0002-2073-412X
|b 0
245 _ _ |a Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.
260 _ _ |a [London]
|c 2025
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 7 |a Batten Disease
|2 Other
650 _ 7 |a DNA Damage
|2 Other
650 _ 7 |a Lysosome-Nucleus Communication
|2 Other
650 _ 7 |a Lysosomes
|2 Other
650 _ 7 |a YAP1
|2 Other
650 _ 7 |a YAP-Signaling Proteins
|2 NLM Chemicals
650 _ 7 |a Adaptor Proteins, Signal Transducing
|2 NLM Chemicals
650 _ 7 |a YAP1 protein, human
|2 NLM Chemicals
650 _ 7 |a Proto-Oncogene Proteins c-abl
|0 EC 2.7.10.2
|2 NLM Chemicals
650 _ 7 |a Membrane Glycoproteins
|2 NLM Chemicals
650 _ 7 |a Molecular Chaperones
|2 NLM Chemicals
650 _ 7 |a CLN3 protein, human
|2 NLM Chemicals
650 _ 7 |a Yap1 protein, mouse
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a YAP-Signaling Proteins
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Apoptosis: genetics
|2 MeSH
650 _ 2 |a Adaptor Proteins, Signal Transducing: metabolism
|2 MeSH
650 _ 2 |a Adaptor Proteins, Signal Transducing: genetics
|2 MeSH
650 _ 2 |a Proto-Oncogene Proteins c-abl: metabolism
|2 MeSH
650 _ 2 |a Proto-Oncogene Proteins c-abl: genetics
|2 MeSH
650 _ 2 |a Membrane Glycoproteins: genetics
|2 MeSH
650 _ 2 |a Membrane Glycoproteins: metabolism
|2 MeSH
650 _ 2 |a Molecular Chaperones: genetics
|2 MeSH
650 _ 2 |a Molecular Chaperones: metabolism
|2 MeSH
650 _ 2 |a Neuronal Ceroid-Lipofuscinoses: genetics
|2 MeSH
650 _ 2 |a Neuronal Ceroid-Lipofuscinoses: metabolism
|2 MeSH
650 _ 2 |a Neuronal Ceroid-Lipofuscinoses: pathology
|2 MeSH
650 _ 2 |a Lysosomes: metabolism
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Retinal Pigment Epithelium: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
700 1 _ |a Calcagni', Alessia
|0 0000-0002-1946-5815
|b 1
700 1 _ |a Freire, Sofia
|0 0009-0002-2316-1096
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700 1 _ |a Pires, Joana
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700 1 _ |a Casqueiro, Ricardo
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700 1 _ |a Salazar, Ivan L
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700 1 _ |a Herz, Niculin Joachim
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700 1 _ |a Huynh, Tuong
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700 1 _ |a Wieciorek, Katarzyna
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700 1 _ |a Outeiro, Tiago Fleming
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700 1 _ |a Girão, Henrique
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700 1 _ |a Milosevic, Ira
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700 1 _ |a Ballabio, Andrea
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700 1 _ |a Raimundo, Nuno
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773 _ _ |a 10.1038/s44319-025-00613-3
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