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000282964 1001_ $$00000-0002-2073-412X$$aDomingues, Neuza$$b0
000282964 245__ $$aLoss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.
000282964 260__ $$a[London]$$bNature Publishing Group UK$$c2025
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000282964 520__ $$aBatten 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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000282964 650_7 $$2Other$$aBatten Disease
000282964 650_7 $$2Other$$aDNA Damage
000282964 650_7 $$2Other$$aLysosome-Nucleus Communication
000282964 650_7 $$2Other$$aLysosomes
000282964 650_7 $$2Other$$aYAP1
000282964 650_7 $$2NLM Chemicals$$aYAP-Signaling Proteins
000282964 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000282964 650_7 $$2NLM Chemicals$$aYAP1 protein, human
000282964 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aProto-Oncogene Proteins c-abl
000282964 650_7 $$2NLM Chemicals$$aMembrane Glycoproteins
000282964 650_7 $$2NLM Chemicals$$aMolecular Chaperones
000282964 650_7 $$2NLM Chemicals$$aCLN3 protein, human
000282964 650_7 $$2NLM Chemicals$$aYap1 protein, mouse
000282964 650_2 $$2MeSH$$aAnimals
000282964 650_2 $$2MeSH$$aYAP-Signaling Proteins
000282964 650_2 $$2MeSH$$aHumans
000282964 650_2 $$2MeSH$$aSignal Transduction
000282964 650_2 $$2MeSH$$aMice
000282964 650_2 $$2MeSH$$aApoptosis: genetics
000282964 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: metabolism
000282964 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: genetics
000282964 650_2 $$2MeSH$$aProto-Oncogene Proteins c-abl: metabolism
000282964 650_2 $$2MeSH$$aProto-Oncogene Proteins c-abl: genetics
000282964 650_2 $$2MeSH$$aMembrane Glycoproteins: genetics
000282964 650_2 $$2MeSH$$aMembrane Glycoproteins: metabolism
000282964 650_2 $$2MeSH$$aMolecular Chaperones: genetics
000282964 650_2 $$2MeSH$$aMolecular Chaperones: metabolism
000282964 650_2 $$2MeSH$$aNeuronal Ceroid-Lipofuscinoses: genetics
000282964 650_2 $$2MeSH$$aNeuronal Ceroid-Lipofuscinoses: metabolism
000282964 650_2 $$2MeSH$$aNeuronal Ceroid-Lipofuscinoses: pathology
000282964 650_2 $$2MeSH$$aLysosomes: metabolism
000282964 650_2 $$2MeSH$$aMice, Knockout
000282964 650_2 $$2MeSH$$aRetinal Pigment Epithelium: metabolism
000282964 650_2 $$2MeSH$$aDisease Models, Animal
000282964 7001_ $$00000-0002-1946-5815$$aCalcagni', Alessia$$b1
000282964 7001_ $$00009-0002-2316-1096$$aFreire, Sofia$$b2
000282964 7001_ $$aPires, Joana$$b3
000282964 7001_ $$00000-0001-8808-9756$$aCasqueiro, Ricardo$$b4
000282964 7001_ $$00000-0001-9667-6766$$aSalazar, Ivan L$$b5
000282964 7001_ $$aHerz, Niculin Joachim$$b6
000282964 7001_ $$00000-0002-5595-419X$$aHuynh, Tuong$$b7
000282964 7001_ $$aWieciorek, Katarzyna$$b8
000282964 7001_ $$0P:(DE-2719)2814138$$aOuteiro, Tiago Fleming$$b9
000282964 7001_ $$00000-0002-5786-8447$$aGirão, Henrique$$b10
000282964 7001_ $$00000-0001-6440-3763$$aMilosevic, Ira$$b11
000282964 7001_ $$00000-0003-1381-4604$$aBallabio, Andrea$$b12
000282964 7001_ $$00000-0002-5988-9129$$aRaimundo, Nuno$$b13
000282964 773__ $$0PERI:(DE-600)2025376-X$$a10.1038/s44319-025-00613-3$$gVol. 26, no. 24, p. 6096 - 6120$$n24$$p6096 - 6120$$tEMBO reports$$v26$$x1469-221X$$y2025
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