Loss of the Lysosomal Protein CLN3 Triggers C-Abl-Dependent YAP1 Pro-Apoptotic Signaling

Authors

• Neuza Domingues
• Alessia Calcagni'
• Sofia Freire
• Joana Pires
• Ricardo Casqueiro
• Ivan L Salazar
• Niculin Joachim Herz
• Tuong Huynh
• Katarzyna Wieciorek
• Tiago Fleming Outeiro
• Henrique Girão
• Ira Milosevic
• Andrea Ballabio
• Nuno Raimundo

Language

English

Publication Date

12-1-2025

Journal

EMBO Reports

DOI

10.1038/s44319-025-00613-3

PMID

41198904

PMCID

PMC12714701

PubMedCentral® Posted Date

11-6-2025

PubMedCentral® Full Text Version

Post-print

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

Animals, YAP-Signaling Proteins, Humans, Signal Transduction, Mice, Apoptosis, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-abl, Membrane Glycoproteins, Molecular Chaperones, Neuronal Ceroid-Lipofuscinoses, Lysosomes, Mice, Knockout, Retinal Pigment Epithelium, Disease Models, Animal, Lysosomes, Batten Disease, Lysosome-Nucleus Communication, YAP1, DNA Damage, Autophagy & Cell Death, Molecular Biology of Disease, Neuroscience

Published Open-Access

yes

Recommended Citation

Domingues, Neuza; Calcagni', Alessia; Freire, Sofia; et al., "Loss of the Lysosomal Protein CLN3 Triggers C-Abl-Dependent YAP1 Pro-Apoptotic Signaling" (2025). Duncan NRI Faculty and Staff Publications. 199.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/199